henekalab.bib

@article{pmid27153489,
  author = {Heneka, M. T.  and Nicotera, P. },
  title = {{{T}houghts on {O}besity and {B}rain {G}lucose}},
  journal = {Cell},
  year = {2016},
  volume = {165},
  number = {4},
  pages = {773--775},
  month = {May},
  abstract = {Homeostatic control of brain metabolism is essential for neuronal activity. Jais et al., (2016) report that reduced brain glucose uptake elicited by a high-fat diet self-corrects by the recruitment of peripheral, VEGF-producing macrophages to the blood-brain barrier. Their findings further suggest that restoring brain glucose availability might help protect from cognitive impairment in Alzheimer's disease.},
  note = {[DOI:\href{http://dx.doi.org/10.1016/j.cell.2016.04.057}{10.1016/j.cell.2016.04.057}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/27153489}{27153489}] }
}
@article{pmid27053774,
  author = {Zimmer, S.  and Grebe, A.  and Bakke, S. S.  and Bode, N.  and Halvorsen, B.  and Ulas, T.  and Skjelland, M.  and De Nardo, D.  and Labzin, L. I.  and Kerksiek, A.  and Hempel, C.  and Heneka, M. T.  and Hawxhurst, V.  and Fitzgerald, M. L.  and Trebicka, J.  and Bjorkhem, I.  and Gustafsson, J. A.  and Westerterp, M.  and Tall, A. R.  and Wright, S. D.  and Espevik, T.  and Schultze, J. L.  and Nickenig, G.  and Lutjohann, D.  and Latz, E. },
  title = {{{C}yclodextrin promotes atherosclerosis regression via macrophage reprogramming}},
  journal = {Sci Transl Med},
  year = {2016},
  volume = {8},
  number = {333},
  pages = {333ra50},
  month = {Apr},
  abstract = {Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol concentrations. Despite ongoing advances in the prevention and treatment of atherosclerosis, cardiovascular disease remains the leading cause of death worldwide. Continuous retention of apolipoprotein B-containing lipoproteins in the subendothelial space causes a local overabundance of free cholesterol. Because cholesterol accumulation and deposition of cholesterol crystals (CCs) trigger a complex inflammatory response, we tested the efficacy of the cyclic oligosaccharide 2-hydroxypropyl-β-cyclodextrin (CD), a compound that increases cholesterol solubility in preventing and reversing atherosclerosis. We showed that CD treatment of murine atherosclerosis reduced atherosclerotic plaque size and CC load and promoted plaque regression even with a continued cholesterol-rich diet. Mechanistically, CD increased oxysterol production in both macrophages and human atherosclerotic plaques and promoted liver X receptor (LXR)-mediated transcriptional reprogramming to improve cholesterol efflux and exert anti-inflammatory effects. In vivo, this CD-mediated LXR agonism was required for the antiatherosclerotic and anti-inflammatory effects of CD as well as for augmented reverse cholesterol transport. Because CD treatment in humans is safe and CD beneficially affects key mechanisms of atherogenesis, it may therefore be used clinically to prevent or treat human atherosclerosis.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878149}{PMC4878149}] [DOI:\href{http://dx.doi.org/10.1126/scitranslmed.aad6100}{10.1126/scitranslmed.aad6100}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/27053774}{27053774}] }
}
@article{pmid26941262,
  author = {Suarez-Calvet, M.  and Kleinberger, G.  and Araque Caballero, M. A.  and Brendel, M.  and Rominger, A.  and Alcolea, D.  and Fortea, J.  and Lleo, A.  and Blesa, R.  and Gispert, J. D.  and Sanchez-Valle, R.  and Antonell, A.  and Rami, L.  and Molinuevo, J. L.  and Brosseron, F.  and Traschutz, A.  and Heneka, M. T.  and Struyfs, H.  and Engelborghs, S.  and Sleegers, K.  and Van Broeckhoven, C.  and Zetterberg, H.  and Nellgard, B.  and Blennow, K.  and Crispin, A.  and Ewers, M.  and Haass, C. },
  title = {{s{T}{R}{E}{M}2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early-stage {A}lzheimer's disease and associate with neuronal injury markers}},
  journal = {EMBO Mol Med},
  year = {2016},
  volume = {8},
  number = {5},
  pages = {466--476},
  abstract = {TREM2 is an innate immune receptor expressed on the surface of microglia. Loss-of-function mutations of TREM2 are associated with increased risk of Alzheimer's disease (AD). TREM2 is a type-1 protein with an ectodomain that is proteolytically cleaved and released into the extracellular space as a soluble variant (sTREM2), which can be measured in the cerebrospinal fluid (CSF). In this cross-sectional multicenter study, we investigated whether CSF levels of sTREM2 are changed during the clinical course of AD, and in cognitively normal individuals with suspected non-AD pathology (SNAP). CSF sTREM2 levels were higher in mild cognitive impairment due to AD than in all other AD groups and controls. SNAP individuals also had significantly increased CSF sTREM2 compared to controls. Moreover, increased CSF sTREM2 levels were associated with higher CSF total tau and phospho-tau181P, which are markers of neuronal degeneration and tau pathology. Our data demonstrate that CSF sTREM2 levels are increased in the early symptomatic phase of AD, probably reflecting a corresponding change of the microglia activation status in response to neuronal degeneration.},
  note = {[DOI:\href{http://dx.doi.org/10.15252/emmm.201506123}{10.15252/emmm.201506123}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/26941262}{26941262}] }
}
@article{pmid26567746,
  author = {Tejera, D.  and Heneka, M. T. },
  title = {{{M}icroglia in {A}lzheimer's disease: the good, the bad and the ugly}},
  journal = {Curr Alzheimer Res},
  year = {2015},
  pages = { },
  month = {Nov},
  abstract = {Traditionally the brain has been viewed as being an immune-privileged organ. However, endogenous stimuli such as the presence of misfolded or aggregated proteins, as well as systemic inflammatory events may lead to the activation of microglial cells, the brain´s innate immune system, and, subsequently, to neuroinflammation. Alzheimer's disease, the leading cause of dementia, is characterized by amyloid beta deposition and tau hyperphosphorylation. Neuroinflammation in Alzheimer's disease has been identified as major contributor to disease pathogenesis. Once activated, microglia release several pro and anti-inflammatory mediators of which several affect the function and structure of the brain. Modulation of this microglial activation in Alzheimer's disease might open new therapeutic avenues.},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/26567746}{26567746}] }
}
@article{pmid26516630,
  author = {Traschutz, A.  and Tzaridis, T.  and Penner, A. H.  and Kuchelmeister, K.  and Urbach, H.  and Hattingen, E.  and Heneka, M. T. },
  title = {{{R}eduction of microbleeds by immunosuppression in a patient with {A}β-related vascular inflammation}},
  journal = {Neurol Neuroimmunol Neuroinflamm},
  year = {2015},
  volume = {2},
  number = {6},
  pages = {e165},
  month = {Dec},
  abstract = {To investigate whether the occurrence or clearance of microhemorrhages in cerebral amyloid angiopathy (CAA)-related vascular inflammation can be modified by immunosuppressive treatment.\\ Clinical and radiologic follow-up for more than 5 years of a patient with histopathologically confirmed CAA-related vascular inflammation treated with a prolonged and tapered regimen of IV cyclophosphamide and oral steroids.\\ Under long-term immunosuppressive treatment, a reduced number of cortical micobleeds was observed on repeat MRIs because of both the prevention of new microbleeds and the clearance of those existing at baseline.\\ Sustained immunosuppression should be considered and systematically investigated as a treatment option for cortical microbleeds in CAA and related inflammatory phenotypes.\\ This study provides Class IV evidence. This is a single observational study without controls.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608757}{PMC4608757}] [DOI:\href{http://dx.doi.org/10.1212/NXI.0000000000000165}{10.1212/NXI.0000000000000165}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/26516630}{26516630}] }
}
@article{pmid26322584,
  author = {Willem, M.  and Tahirovic, S.  and Busche, M. A.  and Ovsepian, S. V.  and Chafai, M.  and Kootar, S.  and Hornburg, D.  and Evans, L. D.  and Moore, S.  and Daria, A.  and Hampel, H.  and Muller, V.  and Giudici, C.  and Nuscher, B.  and Wenninger-Weinzierl, A.  and Kremmer, E.  and Heneka, M. T.  and Thal, D. R.  and Giedraitis, V.  and Lannfelt, L.  and Muller, U.  and Livesey, F. J.  and Meissner, F.  and Herms, J.  and Konnerth, A.  and Marie, H.  and Haass, C. },
  title = {{η-{S}ecretase processing of {A}{P}{P} inhibits neuronal activity in the hippocampus}},
  journal = {Nature},
  year = {2015},
  volume = {526},
  number = {7573},
  pages = {443--447},
  month = {Oct},
  abstract = {Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-β peptide. Two principal physiological pathways either prevent or promote amyloid-β generation from its precursor, β-amyloid precursor protein (APP), in a competitive manner. Although APP processing has been studied in great detail, unknown proteolytic events seem to hinder stoichiometric analyses of APP metabolism in vivo. Here we describe a new physiological APP processing pathway, which generates proteolytic fragments capable of inhibiting neuronal activity within the hippocampus. We identify higher molecular mass carboxy-terminal fragments (CTFs) of APP, termed CTF-η, in addition to the long-known CTF-α and CTF-β fragments generated by the α- and β-secretases ADAM10 (a disintegrin and metalloproteinase 10) and BACE1 (β-site APP cleaving enzyme 1), respectively. CTF-η generation is mediated in part by membrane-bound matrix metalloproteinases such as MT5-MMP, referred to as η-secretase activity. η-Secretase cleavage occurs primarily at amino acids 504-505 of APP695, releasing a truncated ectodomain. After shedding of this ectodomain, CTF-η is further processed by ADAM10 and BACE1 to release long and short Aη peptides (termed Aη-α and Aη-β). CTFs produced by η-secretase are enriched in dystrophic neurites in an AD mouse model and in human AD brains. Genetic and pharmacological inhibition of BACE1 activity results in robust accumulation of CTF-η and Aη-α. In mice treated with a potent BACE1 inhibitor, hippocampal long-term potentiation was reduced. Notably, when recombinant or synthetic Aη-α was applied on hippocampal slices ex vivo, long-term potentiation was lowered. Furthermore, in vivo single-cell two-photon calcium imaging showed that hippocampal neuronal activity was attenuated by Aη-α. These findings not only demonstrate a major functionally relevant APP processing pathway, but may also indicate potential translational relevance for therapeutic strategies targeting APP processing.},
  note = {[DOI:\href{http://dx.doi.org/10.1038/nature14864}{10.1038/nature14864}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/26322584}{26322584}] }
}
@article{pmid26168044,
  author = {Bach, J. P.  and Gold, M.  and Mengel, D.  and Hattesohl, A.  and Lubbe, D.  and Schmid, S.  and Tackenberg, B.  and Rieke, J.  and Maddula, S.  and Baumbach, J. I.  and Nell, C.  and Boeselt, T.  and Michelis, J.  and Alferink, J.  and Heneka, M.  and Oertel, W.  and Jessen, F.  and Janciauskiene, S.  and Vogelmeier, C.  and Dodel, R.  and Koczulla, A. R. },
  title = {{M}easuring {C}ompounds in {E}xhaled {A}ir to {D}etect {A}lzheimer's {D}isease and {P}arkinson's {D}isease},
  journal = {PLoS ONE},
  year = {2015},
  volume = {10},
  number = {7},
  pages = {e0132227},
  abstract = {Alzheimer's disease (AD) is diagnosed based upon medical history, neuropsychiatric examination, cerebrospinal fluid analysis, extensive laboratory analyses and cerebral imaging. Diagnosis is time consuming and labour intensive. Parkinson's disease (PD) is mainly diagnosed on clinical grounds.\\ The primary aim of this study was to differentiate patients suffering from AD, PD and healthy controls by investigating exhaled air with the electronic nose technique. After demonstrating a difference between the three groups the secondary aim was the identification of specific substances responsible for the difference(s) using ion mobility spectroscopy. Thirdly we analysed whether amyloid beta (Aβ) in exhaled breath was causative for the observed differences between patients suffering from AD and healthy controls.\\ We employed novel pulmonary diagnostic tools (electronic nose device/ion-mobility spectrometry) for the identification of patients with neurodegenerative diseases. Specifically, we analysed breath pattern differences in exhaled air of patients with AD, those with PD and healthy controls using the electronic nose device (eNose). Using ion mobility spectrometry (IMS), we identified the compounds responsible for the observed differences in breath patterns. We applied ELISA technique to measure Aβ in exhaled breath condensates.\\ The eNose was able to differentiate between AD, PD and HC correctly. Using IMS, we identified markers that could be used to differentiate healthy controls from patients with AD and PD with an accuracy of 94\%. In addition, patients suffering from PD were identified with sensitivity and specificity of 100\%. Altogether, 3 AD patients out of 53 participants were misclassified. Although we found Aβ in exhaled breath condensate from both AD and healthy controls, no significant differences between groups were detected.\\ These data may open a new field in the diagnosis of neurodegenerative disease such as Alzheimer's disease and Parkinson's disease. Further research is required to evaluate the significance of these pulmonary findings with respect to the pathophysiology of neurodegenerative disorders.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500505}{PMC4500505}] [DOI:\href{http://dx.doi.org/10.1371/journal.pone.0132227}{10.1371/journal.pone.0132227}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/26168044}{26168044}] }
}
@article{pmid25689443,
  author = {Heneka, M. T.  and Golenbock, D. T.  and Latz, E. },
  title = {{I}nnate immunity in {A}lzheimer's disease},
  journal = {Nat. Immunol.},
  year = {2015},
  volume = {16},
  number = {3},
  pages = {229--236},
  month = {Feb},
  abstract = {Alzheimer's disease (AD) is the world's most common dementing illness, affecting over 150 million patients. Classically AD has been viewed as a neurodegenerative disease of the elderly, characterized by the extracellular deposition of misfolded amyloid-$\textbeta$ (A$\textbeta$) peptide and the intracellular formation of neurofibrillary tangles. Only recently has neuroinflammation emerged as an important component of AD pathology. Experimental, genetic and epidemiological data now indicate a crucial role for activation of the innate immune system as a disease-promoting factor. The sustained formation and deposition of A$\textbeta$ aggregates causes chronic activation of the immune system and disturbance of microglial clearance functions. Here we review advances in the molecular understanding of the inflammatory response in AD that point to novel therapeutic approaches for the treatment of this devastating disease.},
  note = {[DOI:\href{http://dx.doi.org/10.1038/ni.3102}{10.1038/ni.3102}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/25689443}{25689443}] }
}
@article{pmid25681414,
  author = {Kurzwelly, D.  and Kruger, S.  and Biskup, S.  and Heneka, M. T. },
  title = {{A} distinct clinical phenotype in a {G}erman kindred with motor neuron disease carrying a {C}{H}{C}{H}{D}10 mutation},
  journal = {Brain},
  year = {2015},
  pages = { },
  month = {Feb},
  note = {[DOI:\href{http://dx.doi.org/10.1093/brain/awv014}{10.1093/brain/awv014}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/25681414}{25681414}] }
}
@article{pmid25500888,
  author = {Krauthausen, M.  and Kummer, M. P.  and Zimmermann, J.  and Reyes-Irisarri, E.  and Terwel, D.  and Bulic, B.  and Heneka, M. T.  and Muller, M. },
  title = {{C}{X}{C}{R}3 promotes plaque formation and behavioral deficits in an {A}lzheimer's disease model},
  journal = {J. Clin. Invest.},
  year = {2014},
  pages = { },
  month = {Dec},
  abstract = {Chemokines are important modulators of neuroinflammation and neurodegeneration. In the brains of Alzheimer's disease (AD) patients and in AD animal models, the chemokine CXCL10 is found in high concentrations, suggesting a pathogenic role for this chemokine and its receptor, CXCR3. Recent studies aimed at addressing the role of CXCR3 in neurological diseases indicate potent, but diverse, functions for CXCR3. Here, we examined the impact of CXCR3 in the amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model of AD. We found that, compared with control APP/PSI animals, plaque burden and Aβ levels were strongly reduced in CXCR3-deficient APP/PS1 mice. Analysis of microglial phagocytosis in vitro and in vivo demonstrated that CXCR3 deficiency increased the microglial uptake of A$\textbeta$. Application of a CXCR3 antagonist increased microglial Aβ phagocytosis, which was associated with reduced TNF-α secretion. Moreover, in CXCR3-deficient APP/PS1 mice, microglia exhibited morphological activation and reduced plaque association, and brain tissue from APP/PS1 animals lacking CXCR3 had reduced concentrations of proinflammatory cytokines compared with controls. Further, loss of CXCR3 attenuated the behavioral deficits observed in APP/PS1 mice. Together, our data indicate that CXCR3 signaling mediates development of AD-like pathology in APP/PS1 mice and suggest that CXCR3 has potential as a therapeutic target for AD.},
  note = {[DOI:\href{http://dx.doi.org/10.1172/JCI66771}{10.1172/JCI66771}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/25500888}{25500888}] }
}
@article{pmid25471190,
  author = {Meiberth, D.  and Scheef, L.  and Wolfsgruber, S.  and Boecker, H.  and Block, W.  and Traber, F.  and Erk, S.  and Heneka, M. T.  and Jacobi, H.  and Spottke, A.  and Walter, H.  and Wagner, M.  and Hu, X.  and Jessen, F. },
  title = {{C}ortical {T}hinning in {I}ndividuals with {S}ubjective {M}emory {I}mpairment},
  journal = {J. Alzheimers Dis.},
  year = {2014},
  pages = { },
  month = {Dec},
  abstract = {Elderly individuals with subjective memory impairment (SMI) report memory decline, but perform within the age-, gender-, and education-adjusted normal range on neuropsychological tests. Longitudinal studies indicate SMI as a risk factor or early sign of Alzheimer's disease (AD). There is increasing evidence from neuroimaging that at the group level, subjects with SMI display evidence of AD-related pathology. This study aimed to determine differences in cortical thickness between individuals with SMI and healthy control subjects (CO) using the FreeSurfer environment. 110 participants (41 SMI/69 CO) underwent structural 3D-T1 MR imaging. Cortical thickness values were compared between groups in predefined AD-related brain regions of the medial temporal lobe, namely the bilateral entorhinal cortex and bilateral parahippocampal cortex. Cortical thickness reduction was observed in the SMI group compared to controls in the left entorhinal cortex (p = 0.012). We interpret our findings as evidence of early AD-related brain changes in persons with SMI.},
  note = {[DOI:\href{http://dx.doi.org/10.3233/JAD-142322}{10.3233/JAD-142322}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/25471190}{25471190}] }
}
@article{pmid25231518,
  author = {Widmann, C. N.  and Schewe, J. C.  and Heneka, M. T. },
  title = {{S}epsis-associated encephalopathy versus sepsis-induced encephalopathy--authors' reply},
  journal = {Lancet Neurol},
  year = {2014},
  volume = {13},
  number = {10},
  pages = {968--969},
  month = {Oct},
  note = {[DOI:\href{http://dx.doi.org/10.1016/S1474-4422(14)70204-2}{10.1016/S1474-4422(14)70204-2}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/25231518}{25231518}] }
}
@article{pmid25071159,
  author = {Heneka, M. T. },
  title = {{M}acrophages derived from infiltrating monocytes mediate autoimmune myelin destruction},
  journal = {J. Exp. Med.},
  year = {2014},
  volume = {211},
  number = {8},
  pages = {1500},
  month = {Jul},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113949}{PMC4113949}] [DOI:\href{http://dx.doi.org/10.1084/jem.2118insight1}{10.1084/jem.2118insight1}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/25071159}{25071159}] }
}
@article{pmid25042114,
  author = {Thelen, M.  and Razquin, C.  and Hernandez, I.  and Gorostidi, A.  and Sanchez-Valle, R.  and Ortega-Cubero, S.  and Wolfsgruber, S.  and Drichel, D.  and Fliessbach, K.  and Duenkel, T.  and Damian, M.  and Heilmann, S.  and Slotosch, A.  and Lennarz, M.  and Seijo-Martinez, M.  and Rene, R.  and Kornhuber, J.  and Peters, O.  and Luckhaus, C.  and Jahn, H.  and Hull, M.  and Ruther, E.  and Wiltfang, J.  and Lorenzo, E.  and Gascon, J.  and Lleo, A.  and Llado, A.  and Campdelacreu, J.  and Moreno, F.  and Ahmadzadehfar, H.  and Fortea, J.  and Indakoetxea, B.  and Heneka, M. T.  and Wetter, A.  and Pastor, M. A.  and Riverol, M.  and Becker, T.  and Frolich, L.  and Tarraga, L.  and Boada, M.  and Wagner, M.  and Jessen, F.  and Maier, W.  and Clarimon, J.  and Lopez de Munain, A.  and Ruiz, A.  and Pastor, P.  and Ramirez, A. },
  title = {{I}nvestigation of the role of rare {T}{R}{E}{M}2 variants in frontotemporal dementia subtypes},
  journal = {Neurobiol. Aging},
  year = {2014},
  volume = {35},
  number = {11},
  pages = {13--19},
  month = {Nov},
  abstract = {Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. Rare TREM2 variants have been recently identified in families affected by FTD-like phenotype. However, genetic studies of the role of rare TREM2 variants in FTD have generated conflicting results possibly because of difficulties on diagnostic accuracy. The aim of the present study was to investigate associations between rare TREM2 variants and specific FTD subtypes (FTD-S). The entire coding sequence of TREM2 was sequenced in FTD-S patients of Spanish (n = 539) and German (n = 63) origin. Genetic association was calculated using Fisher exact test. The minor allele frequency for controls was derived from in-house genotyping data and publicly available databases. Seven previously reported rare coding variants (p.A28V, p.W44X, p.R47H, p.R62H, p.T66M, p.T96K, and p.L211P) and 1 novel missense variant (p.A105T) were identified. The p.R47H variant was found in 4 patients with FTD-S. Two of these patients showed cerebrospinal fluid pattern of amyloid beta, tau, and phosphorylated-tau suggesting underlying Alzheimer's disease (AD) pathology. No association was found between p.R47H and FTD-S. A genetic association was found between p.T96K and FTD-S (p = 0.013, odds ratio = 4.23, 95\% Confidence Interval [1.17-14.77]). All 6 p.T96K patients also carried the TREM2 variant p.L211P, suggesting linkage disequilibrium. The remaining TREM2 variants were found in 1 patient, respectively, and were absent in controls. The present findings provide evidence that p.T96K is associated with FTD-S and that p.L211P may contribute to its pathogenic effect. The data also suggest that p.R47H is associated with an FTD phenotype that is characterized by the presence of underlying AD pathology.},
  note = {[DOI:\href{http://dx.doi.org/10.1016/j.neurobiolaging.2014.06.018}{10.1016/j.neurobiolaging.2014.06.018}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/25042114}{25042114}] }
}
@article{pmid25031638,
  author = {Kummer, M. P.  and Heneka, M. T. },
  title = {{T}runcated and modified amyloid-beta species},
  journal = {Alzheimers Res Ther},
  year = {2014},
  volume = {6},
  number = {3},
  pages = {28},
  abstract = {Alzheimer's disease pathology is closely connected to the processing of the amyloid precursor protein (APP) resulting in the formation of a variety of amyloid-beta (Abeta) peptides. They are found as insoluble aggregates in senile plaques, the histopathological hallmark of the disease. These peptides are also found in soluble, mostly monomeric and dimeric, forms in the interstitial and cerebrospinal fluid. Due to the combination of several enzymatic activities during APP processing, Aβ peptides exist in multiple isoforms possessing different N-termini and C-termini. These peptides include, to a certain extent, part of the juxtamembrane and transmembrane domain of APP. Besides differences in size, post-translational modifications of Aβ - including oxidation, phosphorylation, nitration, racemization, isomerization, pyroglutamylation, and glycosylation - generate a plethora of peptides with different physiological and pathological properties that may modulate disease progression.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4055046}{PMC4055046}] [DOI:\href{http://dx.doi.org/10.1186/alzrt258}{10.1186/alzrt258}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/25031638}{25031638}] }
}
@article{pmid25027320,
  author = {Ramirez, A.  and van der Flier, W. M.  and Herold, C.  and Ramonet, D.  and Heilmann, S.  and Lewczuk, P.  and Popp, J.  and Lacour, A.  and Drichel, D.  and Louwersheimer, E.  and Kummer, M. P.  and Cruchaga, C.  and Hoffmann, P.  and Teunissen, C.  and Holstege, H.  and Kornhuber, J.  and Peters, O.  and Naj, A. C.  and Chouraki, V.  and Bellenguez, C.  and Gerrish, A.  and Heun, R.  and Frolich, L.  and Hull, M.  and Buscemi, L.  and Herms, S.  and Kolsch, H.  and Scheltens, P.  and Breteler, M. M.  and Ruther, E.  and Wiltfang, J.  and Goate, A.  and Jessen, F.  and Maier, W.  and Heneka, M. T.  and Becker, T.  and Nothen, M. M. },
  title = {{S}{U}{C}{L}{G}2 identified as both a determinator of {C}{S}{F} {A}beta1-42 levels and an attenuator of cognitive decline in {A}lzheimer's disease},
  journal = {Hum. Mol. Genet.},
  year = {2014},
  volume = {23},
  number = {24},
  pages = {6644--6658},
  month = {Dec},
  abstract = {Cerebrospinal fluid amyloid-beta 1-42 (Aβ1-42) and phosphorylated Tau at position 181 (pTau181) are biomarkers of Alzheimer's disease (AD). We performed an analysis and meta-analysis of genome-wide association study data on Aβ1-42 and pTau181 in AD dementia patients followed by independent replication. An association was found between Abeta1-42 level and a single-nucleotide polymorphism in SUCLG2 (rs62256378) (P = 2.5×10(-12)). An interaction between APOE genotype and rs62256378 was detected (P = 9.5 × 10(-5)), with the strongest effect being observed in APOE-ε4 noncarriers. Clinically, rs62256378 was associated with rate of cognitive decline in AD dementia patients (P = 3.1 × 10(-3)). Functional microglia experiments showed that SUCLG2 was involved in clearance of Aβ1-42.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240204}{PMC4240204}] [DOI:\href{http://dx.doi.org/10.1093/hmg/ddu372}{10.1093/hmg/ddu372}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/25027320}{25027320}] }
}
@article{pmid24997987,
  author = {Gockel, I.  and Becker, J.  and Wouters, M. M.  and Niebisch, S.  and Gockel, H. R.  and Hess, T.  and Ramonet, D.  and Zimmermann, J.  and Vigo, A. G.  and Trynka, G.  and de Leon, A. R.  and de la Serna, J. P.  and Urcelay, E.  and Kumar, V.  and Franke, L.  and Westra, H. J.  and Drescher, D.  and Kneist, W.  and Marquardt, J. U.  and Galle, P. R.  and Mattheisen, M.  and Annese, V.  and Latiano, A.  and Fumagalli, U.  and Laghi, L.  and Cuomo, R.  and Sarnelli, G.  and Muller, M.  and Eckardt, A. J.  and Tack, J.  and Hoffmann, P.  and Herms, S.  and Mangold, E.  and Heilmann, S.  and Kiesslich, R.  and von Rahden, B. H.  and Allescher, H. D.  and Schulz, H. G.  and Wijmenga, C.  and Heneka, M. T.  and Lang, H.  and Hopfner, K. P.  and Nothen, M. M.  and Boeckxstaens, G. E.  and de Bakker, P. I.  and Knapp, M.  and Schumacher, J. },
  title = {{C}ommon variants in the {H}{L}{A}-{D}{Q} region confer susceptibility to idiopathic achalasia},
  journal = {Nat. Genet.},
  year = {2014},
  volume = {46},
  number = {8},
  pages = {901--904},
  month = {Aug},
  abstract = {Idiopathic achalasia is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus. This ultimately leads to massive dilatation and an irreversibly impaired megaesophagus. We performed a genetic association study in 1,068 achalasia cases and 4,242 controls and fine-mapped a strong MHC association signal by imputing classical HLA haplotypes and amino acid polymorphisms. An eight-residue insertion at position 227-234 in the cytoplasmic tail of HLA-DQβ1 (encoded by HLA-DQB1*05:03 and HLA-DQB1*06:01) confers the strongest risk for achalasia (P=1.73×10(-19)). In addition, two amino acid substitutions in the extracellular domain of HLA-DQα1 at position 41 (lysine encoded by HLA-DQA1*01:03; P=5.60×10(-10)) and of HLA-DQβ1 at position 45 (glutamic acid encoded by HLA-DQB1*03:01 and HLA-DQB1*03:04; P=1.20×10(-9)) independently confer achalasia risk. Our study implies that immune-mediated processes are involved in the pathophysiology of achalasia.},
  note = {[DOI:\href{http://dx.doi.org/10.1038/ng.3029}{10.1038/ng.3029}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/24997987}{24997987}] }
}
@article{pmid24990881,
  author = {Kleinberger, G.  and Yamanishi, Y.  and Suarez-Calvet, M.  and Czirr, E.  and Lohmann, E.  and Cuyvers, E.  and Struyfs, H.  and Pettkus, N.  and Wenninger-Weinzierl, A.  and Mazaheri, F.  and Tahirovic, S.  and Lleo, A.  and Alcolea, D.  and Fortea, J.  and Willem, M.  and Lammich, S.  and Molinuevo, J. L.  and Sanchez-Valle, R.  and Antonell, A.  and Ramirez, A.  and Heneka, M. T.  and Sleegers, K.  and van der Zee, J.  and Martin, J. J.  and Engelborghs, S.  and Demirtas-Tatlidede, A.  and Zetterberg, H.  and Van Broeckhoven, C.  and Gurvit, H.  and Wyss-Coray, T.  and Hardy, J.  and Colonna, M.  and Haass, C. },
  title = {{T}{R}{E}{M}2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis},
  journal = {Sci Transl Med},
  year = {2014},
  volume = {6},
  number = {243},
  pages = {243ra86},
  month = {Jul},
  abstract = {Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to Nasu-Hakola disease, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and FTD-like syndrome without bone involvement. TREM2 is an innate immune receptor preferentially expressed by microglia and is involved in inflammation and phagocytosis. Whether and how TREM2 missense mutations affect TREM2 function is unclear. We report that missense mutations associated with FTD and FTD-like syndrome reduce TREM2 maturation, abolish shedding by ADAM proteases, and impair the phagocytic activity of TREM2-expressing cells. As a consequence of reduced shedding, TREM2 is virtually absent in the cerebrospinal fluid (CSF) and plasma of a patient with FTD-like syndrome. A decrease in soluble TREM2 was also observed in the CSF of patients with AD and FTD, further suggesting that reduced TREM2 function may contribute to increased risk for two neurodegenerative disorders.},
  note = {[DOI:\href{http://dx.doi.org/10.1126/scitranslmed.3009093}{10.1126/scitranslmed.3009093}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/24990881}{24990881}] }
}
@article{pmid24977265,
  author = {Heneka, M. T. },
  title = {{M}ichael {T}homas {H}eneka},
  journal = {Lancet Neurol},
  year = {2014},
  volume = {13},
  number = {6},
  pages = {542},
  month = {Jun},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/24977265}{24977265}] }
}
@article{pmid24966384,
  author = {Kummer, M. P.  and Hammerschmidt, T.  and Martinez, A.  and Terwel, D.  and Eichele, G.  and Witten, A.  and Figura, S.  and Stoll, M.  and Schwartz, S.  and Pape, H. C.  and Schultze, J. L.  and Weinshenker, D.  and Heneka, M. T. },
  title = {{E}ar2 deletion causes early memory and learning deficits in {A}{P}{P}/{P}{S}1 mice},
  journal = {J. Neurosci.},
  year = {2014},
  volume = {34},
  number = {26},
  pages = {8845--8854},
  month = {Jun},
  abstract = {To assess the consequences of locus ceruleus (LC) degeneration and subsequent noradrenaline (NA) deficiency in early Alzheimer's disease (AD), mice overexpressing mutant amyloid precursor protein and presenilin-1 (APP/PS1) were crossed with Ear2(-/-) mice that have a severe loss of LC neurons projecting to the hippocampus and neocortex. Testing spatial memory and hippocampal long-term potentiation revealed an impairment in APP/PS1 Ear2(-/-) mice, whereas APP/PS1 or Ear2(-/-) mice showed only minor changes. These deficits were associated with distinct synaptic changes including reduced expression of the NMDA 2A subunit and increased levels of NMDA receptor 2B in APP/PS1 Ear2(-/-) mice. Acute pharmacological replacement of NA by L-threo-DOPS partially restored phosphorylation of β-CaMKII and spatial memory performance in APP/PS1 Ear2(-/-) mice. These changes were not accompanied by altered APP processing or amyloid β peptide (Aβ) deposition. Thus, early LC degeneration and subsequent NA reduction may contribute to cognitive deficits via CaMKII and NMDA receptor dysfunction independent of Aβ and suggests that NA supplementation could be beneficial in treating AD.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4147626}{PMC4147626}] [DOI:\href{http://dx.doi.org/10.1523/JNEUROSCI.4027-13.2014}{10.1523/JNEUROSCI.4027-13.2014}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/24966384}{24966384}] }
}
@article{pmid24962261,
  author = {Heneka, M. T.  and Kummer, M. P.  and Latz, E. },
  title = {{I}nnate immune activation in neurodegenerative disease},
  journal = {Nat. Rev. Immunol.},
  year = {2014},
  volume = {14},
  number = {7},
  pages = {463--477},
  month = {Jul},
  abstract = {The triggering of innate immune mechanisms is emerging as a crucial component of major neurodegenerative diseases. Microglia and other cell types in the brain can be activated in response to misfolded proteins or aberrantly localized nucleic acids. This diverts microglia from their physiological and beneficial functions, and leads to their sustained release of pro-inflammatory mediators. In this Review, we discuss how the activation of innate immune signalling pathways - in particular, the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome - by aberrant host proteins may be a common step in the development of diverse neurodegenerative disorders. During chronic activation of microglia, the sustained exposure of neurons to pro-inflammatory mediators can cause neuronal dysfunction and contribute to cell death. As chronic neuroinflammation is observed at relatively early stages of neurodegenerative disease, targeting the mechanisms that drive this process may be useful for diagnostic and therapeutic purposes.},
  note = {[DOI:\href{http://dx.doi.org/10.1038/nri3705}{10.1038/nri3705}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/24962261}{24962261}] }
}
@article{pmid24930935,
  author = {Krauthausen, M.  and Saxe, S.  and Zimmermann, J.  and Emrich, M.  and Heneka, M. T.  and Muller, M. },
  title = {{C}{X}{C}{R}3 modulates glial accumulation and activation in cuprizone-induced demyelination of the central nervous system},
  journal = {J Neuroinflammation},
  year = {2014},
  volume = {11},
  pages = {109},
  abstract = {The functional state of glial cells, like astrocytes and microglia, critically modulates the course of neuroinflammatory and neurodegenerative diseases and can have both detrimental and beneficial effects. Glial cell function is tightly controlled by cellular interactions in which cytokines are important messengers. Recent studies provide evidence that in particular chemokines are important modulators of glial cell function. During the course of CNS diseases like multiple sclerosis or Alzheimer's disease, and in the corresponding animal models, the chemokines CXCL9 and CXCL10 are abundantly expressed at sites of glial activation, arguing for an important role of these chemokines and their corresponding receptor CXCR3 in glial activation. To clarify the role of this chemokine system in glial cell activation, we characterized the impact of CXCR3 on glial activation in a model of toxic demyelination in which glial activation without a prominent influx of hematogenous cells is prototypical.\\ We investigated the impact of CXCR3 on cuprizone-induced demyelination, comparing CXCR3-deficient mice with wild type controls. The clinical course during cuprizone feeding was documented for five weeks and for the subsequent four days withdrawal of the cuprizone diet (5.5 weeks). Glial activation was characterized using histological, histomorphometric and phenotypic analysis. Molecular analysis for (de)myelination and neuroinflammation was applied to characterize the effect of cuprizone on CXCR3-deficient mice and control animals.\\ CXCR3-deficient mice displayed a milder clinical course during cuprizone feeding and a more rapid body weight recovery after offset of diet. In the CNS, CXCR3 deficiency significantly attenuated the accumulation and activation of microglia and astrocytes. Moreover, a deficiency of CXCR3 reduced the expression of the microglial activation markers CD45 and CD11b. Compared to controls, we observed a vast reduction of RNA levels for proinflammatory cytokines and chemokines like Ccl2, Cxcl10, Tnf and Il6 within the CNS of cuprizone-treated mice. Lastly, CXCR3 deficiency had no major effects on the course of demyelination during cuprizone feeding.\\ The CXCR3 chemokine system is critically involved in the intrinsic glial activation during cuprizone-induced demyelination, which significantly modulates the distribution of glial cells and the local cytokine milieu.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096537}{PMC4096537}] [DOI:\href{http://dx.doi.org/10.1186/1742-2094-11-109}{10.1186/1742-2094-11-109}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/24930935}{24930935}] }
}
@article{pmid24899140,
  author = {van der Zee, J.  and Van Langenhove, T.  and Kovacs, G. G.  and Dillen, L.  and Deschamps, W.  and Engelborghs, S.  and Mat?j, R.  and Vandenbulcke, M.  and Sieben, A.  and Dermaut, B.  and Smets, K.  and Van Damme, P.  and Merlin, C.  and Laureys, A.  and Van Den Broeck, M.  and Mattheijssens, M.  and Peeters, K.  and Benussi, L.  and Binetti, G.  and Ghidoni, R.  and Borroni, B.  and Padovani, A.  and Archetti, S.  and Pastor, P.  and Razquin, C.  and Ortega-Cubero, S.  and Hernandez, I.  and Boada, M.  and Ruiz, A.  and de Mendonca, A.  and Miltenberger-Miltenyi, G.  and do Couto, F. S.  and Sorbi, S.  and Nacmias, B.  and Bagnoli, S.  and Graff, C.  and Chiang, H. H.  and Thonberg, H.  and Perneczky, R.  and Diehl-Schmid, J.  and Alexopoulos, P.  and Frisoni, G. B.  and Bonvicini, C.  and Synofzik, M.  and Maetzler, W.  and vom Hagen, J. M.  and Schols, L.  and Haack, T. B.  and Strom, T. M.  and Prokisch, H.  and Dols-Icardo, O.  and Clarimon, J.  and Lleo, A.  and Santana, I.  and Almeida, M. R.  and Santiago, B.  and Heneka, M. T.  and Jessen, F.  and Ramirez, A.  and Sanchez-Valle, R.  and Llado, A.  and Gelpi, E.  and Sarafov, S.  and Tournev, I.  and Jordanova, A.  and Parobkova, E.  and Fabrizi, G. M.  and Testi, S.  and Salmon, E.  and Strobel, T.  and Santens, P.  and Robberecht, W.  and De Jonghe, P.  and Martin, J. J.  and Cras, P.  and Vandenberghe, R.  and De Deyn, P. P.  and Cruts, M.  and Sleegers, K.  and Van Broeckhoven, C. },
  title = {{R}are mutations in {S}{Q}{S}{T}{M}1 modify susceptibility to frontotemporal lobar degeneration},
  journal = {Acta Neuropathol.},
  year = {2014},
  volume = {128},
  number = {3},
  pages = {397--410},
  month = {Sep},
  abstract = {Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency <0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency <0.01, an overall frequency of 3.2 \% was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 \% CI 1.24-3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4131163}{PMC4131163}] [DOI:\href{http://dx.doi.org/10.1007/s00401-014-1298-7}{10.1007/s00401-014-1298-7}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/24899140}{24899140}] }
}
@article{pmid24849863,
  author = {Widmann, C. N.  and Heneka, M. T. },
  title = {{L}ong-term cerebral consequences of sepsis},
  journal = {Lancet Neurol},
  year = {2014},
  volume = {13},
  number = {6},
  pages = {630--636},
  month = {Jun},
  abstract = {Sepsis is a potentially fatal whole-body inflammatory state caused by severe infection, in which a maladaptive, system-wide inflammatory response follows initial attempts to eliminate pathogens, leading to a dangerous and often fatal increase in the permeability of the blood-brain barrier. These changes in the blood-brain barrier might lead to a major symptom of sepsis, sepsis-associated encephalopathy, which manifests as confusion with a rapid decline in cognitive functions, especially memory, or coma. Once presumed to be entirely reversible, research suggests that sepsis-associated encephalopathy could lead to permanent neurocognitive dysfunction and functional impairments, even after the patient has recovered. Sepsis might act as a major inflammatory hit and potentially increase the brain's susceptibility to neurodegenerative disease, further deterioration of cognitive ability, and risk of developing dementia in later life. Key opportunities for neuroprotective interventions and after-care for people who have survived sepsis might be lost because the long-term neurocognitive and functional consequences of sepsis are not fully characterised.},
  note = {[DOI:\href{http://dx.doi.org/10.1016/S1474-4422(14)70017-1}{10.1016/S1474-4422(14)70017-1}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/24849863}{24849863}] }
}
@article{pmid24838579,
  author = {Kummer, M. P.  and Schwarzenberger, R.  and Sayah-Jeanne, S.  and Dubernet, M.  and Walczak, R.  and Hum, D. W.  and Schwartz, S.  and Axt, D.  and Heneka, M. T. },
  title = {{P}an-{P}{P}{A}{R} {M}odulation {E}ffectively {P}rotects {A}{P}{P}/{P}{S}1 {M}ice from {A}myloid {D}eposition and {C}ognitive {D}eficits},
  journal = {Mol. Neurobiol.},
  year = {2014},
  pages = { },
  month = {May},
  abstract = {Alzheimer's disease (AD) is a neurodegenerative condition that leads to neuronal death and memory dysfunction. In the past, specific peroxisome proliferator-activated receptor (PPAR)γ-agonists, such as pioglitazone, have been tested with limited success to improve AD pathology. Here, we investigated the therapeutic efficacy of GFT1803, a novel potent PPAR agonist that activates all the three PPAR isoforms (α/δ/γ) in the APP/PS1 mouse model in comparison to the selective PPARγ-agonist pioglitazone. Both compounds showed similar brain/plasma partitioning ratios, although whole body and brain exposure to GFT1803 was significantly lower as compared to pioglitazone, at doses used in this study. Oral treatment of APP/PS1 mice with GFT1803 decreased microglial activation, amyloid β (Aβ) plaque area, Aβ levels in sodium dodecyl sulfate- and formic acid-soluble fractions in a concentration-dependent manner. With a single exception of Aβ38 and Aβ40 levels, measured by ELISA, these effects were not observed in mice treated with pioglitazone. Both ligands decreased glial fibrillary acidic protein (GFAP) expression to similar extent and did not affect ApoE expression. Finally, GFT1803 increased insulin-degrading enzyme expression. Analysis of spatial memory formation in the Morris water maze demonstrated that both compounds were able to partially revert the phenotype of APP/PS1 mice in comparison to wild-type mice with GFT1803 being most effective. As compared to pioglitazone, GFT1803 (pan-PPAR agonist) produced both quantitatively superior and qualitatively different therapeutic effects with respect to amyloid plaque burden, insoluble Aβ content, and neuroinflammation at significantly lower whole body and brain exposure rates.},
  note = {[DOI:\href{http://dx.doi.org/10.1007/s12035-014-8743-4}{10.1007/s12035-014-8743-4}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/24838579}{24838579}] }
}
@article{pmid24724819,
  author = {Lindlau, A.  and Widmann, C. N.  and Putensen, C.  and Jessen, F.  and Semmler, A.  and Heneka, M. T. },
  title = {{P}redictors of hippocampal atrophy in critically ill patients},
  journal = {Eur. J. Neurol.},
  year = {2014},
  pages = { },
  month = {Apr},
  abstract = {Hippocampal atrophy is presumably one morphological sign of critical illness encephalopathy; however, predictors have not yet been determined.\\ The data for this report derived from patients treated at the intensive care units (ICUs) of the University Hospital in Bonn in the years 2004-2006. These patients underwent structural magnetic resonance imaging 6-24 months after discharge. Volumes (intracranial, whole brain, white matter, grey matter, cerebral spinal fluid, bilateral hippocampus) were compared with healthy controls. Pro-inflammatory parameters and ICU scoring systems were explored in conjunction with brain volumes. Cut-scores were defined to differentiate patients with high from those with low inflammatory response.\\ Hippocampal and white matter volume were reduced in critically ill patients compared with healthy controls. Procalcitonin showed a very strong correlation (r = -0.903, P = 0.01) and interleukin-6 a moderate correlation (r = -0.538, P = 0.031) with hippocampal volume, but not with other brain volumes. C-reactive protein was linked to grey matter volume. There was no correlation with systemic inflammatory response syndrome criteria (body temperature, heart rate, respiratory rate, white blood cell count) or for hippocampal or whole brain volume. Furthermore, parameters representing severity of disease (APACHE II score, SOFA score, duration of stay and duration of mechanical ventilation) were not associated with hippocampal or other brain volumes.\\ This analysis suggests that high levels of procalcitonin and interleukin-6 in the blood serum of critically ill patients are associated with a high likelihood of hippocampal atrophy irrespective of the severity of disease measured by ICU scoring systems and other inflammatory parameters.},
  note = {[DOI:\href{http://dx.doi.org/10.1111/ene.12443}{10.1111/ene.12443}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/24724819}{24724819}] }
}
@article{pmid24567119,
  author = {Brosseron, F.  and Krauthausen, M.  and Kummer, M.  and Heneka, M. T. },
  title = {{B}ody fluid cytokine levels in mild cognitive impairment and {A}lzheimer's disease: a comparative overview},
  journal = {Mol. Neurobiol.},
  year = {2014},
  volume = {50},
  number = {2},
  pages = {534--544},
  month = {Oct},
  abstract = {This article gives a comprehensive overview of cytokine and other inflammation associated protein levels in plasma, serum and cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI). We reviewed 118 research articles published between 1989 and 2013 to compare the reported levels of 66 cytokines and other proteins related to regulation and signaling in inflammation in the blood or CSF obtained from MCI and AD patients. Several cytokines are evidently regulated in (neuro-) inflammatory processes associated with neurodegenerative disorders. Others do not display changes in the blood or CSF during disease progression. However, many reports on cytokine levels in MCI or AD are controversial or inconclusive, particularly those which provide data on frequently investigated cytokines like tumor necrosis factor alpha (TNF-α) or interleukin-6 (IL-6). The levels of several cytokines are possible indicators of neuroinflammation in AD. Some of them might increase steadily during disease progression or temporarily at the time of MCI to AD conversion. Furthermore, elevated body fluid cytokine levels may correlate with an increased risk of conversion from MCI to AD. Yet, research results are conflicting. To overcome interindividual variances and to obtain a more definite description of cytokine regulation and function in neurodegeneration, a high degree of methodical standardization and patients collective characterization, together with longitudinal sampling over years is essential.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182618}{PMC4182618}] [DOI:\href{http://dx.doi.org/10.1007/s12035-014-8657-1}{10.1007/s12035-014-8657-1}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/24567119}{24567119}] }
}
@article{pmid24067878,
  author = {Stoffels, B.  and Hupa, K. J.  and Snoek, S. A.  and van Bree, S.  and Stein, K.  and Schwandt, T.  and Vilz, T. O.  and Lysson, M.  and Veer, C. V.  and Kummer, M. P.  and Hornung, V.  and Kalff, J. C.  and de Jonge, W. J.  and Wehner, S. },
  title = {{P}ostoperative ileus involves interleukin-1 receptor signaling in enteric glia},
  journal = {Gastroenterology},
  year = {2014},
  volume = {146},
  number = {1},
  pages = {176--187},
  month = {Jan},
  abstract = {Postoperative ileus (POI) is a common consequence of abdominal surgery that increases the risk of postoperative complications and morbidity. We investigated the cellular mechanisms and immune responses involved in the pathogenesis of POI.\\ We studied a mouse model of POI in which intestinal manipulation leads to inflammation of the muscularis externa and disrupts motility. We used C57BL/6 (control) mice as well as mice deficient in Toll-like receptors (TLRs) and cytokine signaling components (TLR-2(-/-), TLR-4(-/-), TLR-2/4(-/-), MyD88(-/-), MyD88/TLR adaptor molecule 1(-/-), interleukin-1 receptor [IL-1R1](-/-), and interleukin (IL)-18(-/-) mice). Bone marrow transplantation experiments were performed to determine which cytokine receptors and cell types are involved in the pathogenesis of POI.\\ Development of POI did not require TLRs 2, 4, or 9 or MyD88/TLR adaptor molecule 2 but did require MyD88, indicating a role for IL-1R1. IL-1R1(-/-) mice did not develop POI; however, mice deficient in IL-18, which also signals via MyD88, developed POI. Mice given injections of an IL-1 receptor antagonist (anakinra) or antibodies to deplete IL-1α and IL-1β before intestinal manipulation were protected from POI. Induction of POI activated the inflammasome in muscularis externa tissues of C57BL6 mice, and IL-1α and IL-1β were released in ex vivo organ bath cultures. In bone marrow transplantation experiments, the development of POI required activation of IL-1 receptor in nonhematopoietic cells. IL-1R1 was expressed by enteric glial cells in the myenteric plexus layer, and cultured primary enteric glia cells expressed IL-6 and the chemokine monocyte chemotactic protein 1 in response to IL-1β stimulation. Immunohistochemical analysis of human small bowel tissue samples confirmed expression of IL-1R1 in the ganglia of the myenteric plexus.\\ IL-1 signaling, via IL-1R1 and MyD88, is required for development of POI after intestinal manipulation in mice. Agents that interfere with the IL-1 signaling pathway are likely to be effective in the treatment of POI.},
  note = {[DOI:\href{http://dx.doi.org/10.1053/j.gastro.2013.09.030}{10.1053/j.gastro.2013.09.030}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/24067878}{24067878}] }
}
@article{pmid23830913,
  author = {Malhotra, A.  and Younesi, E.  and Gundel, M.  and Muller, B.  and Heneka, M. T.  and Hofmann-Apitius, M. },
  title = {{A}{D}{O}: a disease ontology representing the domain knowledge specific to {A}lzheimer's disease},
  journal = {Alzheimers Dement},
  year = {2014},
  volume = {10},
  number = {2},
  pages = {238--246},
  month = {Mar},
  abstract = {Biomedical ontologies offer the capability to structure and represent domain-specific knowledge semantically. Disease-specific ontologies can facilitate knowledge exchange across multiple disciplines, and ontology-driven mining approaches can generate great value for modeling disease mechanisms. However, in the case of neurodegenerative diseases such as Alzheimer's disease, there is a lack of formal representation of the relevant knowledge domain.\\ Alzheimer's disease ontology (ADO) is constructed in accordance to the ontology building life cycle. The Protégé OWL editor was used as a tool for building ADO in Ontology Web Language format.\\ ADO was developed with the purpose of containing information relevant to four main biological views-preclinical, clinical, etiological, and molecular/cellular mechanisms-and was enriched by adding synonyms and references. Validation of the lexicalized ontology by means of named entity recognition-based methods showed a satisfactory performance (F score = 72\%). In addition to structural and functional evaluation, a clinical expert in the field performed a manual evaluation and curation of ADO. Through integration of ADO into an information retrieval environment, we show that the ontology supports semantic search in scientific text. The usefulness of ADO is authenticated by dedicated use case scenarios.\\ Development of ADO as an open ADO is a first attempt to organize information related to Alzheimer's disease in a formalized, structured manner. We demonstrate that ADO is able to capture both established and scattered knowledge existing in scientific text.},
  note = {[DOI:\href{http://dx.doi.org/10.1016/j.jalz.2013.02.009}{10.1016/j.jalz.2013.02.009}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/23830913}{23830913}] }
}
@article{pmid23813380,
  author = {Gaikwad, S. M.  and Heneka, M. T. },
  title = {{S}tudying {M}1 and {M}2 states in adult microglia},
  journal = {Methods Mol. Biol.},
  year = {2013},
  volume = {1041},
  pages = {185--197},
  abstract = {Microglial cell function receives increasing interest. To date, the majority of experiments are performed by using immortalized microglia-like cells or primary microglia prepared from pre- or postnatal rodent brain. As those may not adequately reflect the microglial biology in the adult brain, this protocol advocates a procedure which allows for the isolation, purification, and subsequent analysis of microglial cells. Once isolated, the principal state of activation, M1 or M2, can be determined in adult microglia using fluorescence-activated cell sorting, quantitative PCR, and/or Western blotting. Likewise, adult microglia generated by this protocol can be used for functional analysis through cell cultivation for a limited time.},
  note = {[DOI:\href{http://dx.doi.org/10.1007/978-1-62703-520-0_18}{10.1007/978-1-62703-520-0_18}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/23813380}{23813380}] }
}
@article{pmid23634965,
  author = {Chalermpalanupap, T.  and Kinkead, B.  and Hu, W. T.  and Kummer, M. P.  and Hammerschmidt, T.  and Heneka, M. T.  and Weinshenker, D.  and Levey, A. I. },
  title = {{T}argeting norepinephrine in mild cognitive impairment and {A}lzheimer's disease},
  journal = {Alzheimers Res Ther},
  year = {2013},
  volume = {5},
  number = {2},
  pages = {21},
  abstract = {The Alzheimer's disease (AD) epidemic is a looming crisis, with an urgent need for new therapies to delay or prevent symptom onset and progression. There is growing awareness that clinical trials must target stage-appropriate pathophysiological mechanisms to effectively develop disease-modifying treatments. Advances in AD biomarker research have demonstrated changes in amyloid-beta (Aβ), brain metabolism and other pathophysiologies prior to the onset of memory loss, with some markers possibly changing one or two decades earlier. These findings suggest that amyloid-based therapies would optimally be targeted at the earliest clinically detectable stage (such as mild cognitive impairment (MCI)) or before. Postmortem data indicate that tau lesions in the locus coeruleus (LC), the primary source of subcortical norepinephrine (NE), may be the first identifiable pathology of AD, and recent data from basic research in animal models of AD indicate that loss of NE incites a neurotoxic proinflammatory condition, reduces Aβ clearance and negatively impacts cognition - recapitulating key aspects of AD. In addition, evidence linking NE deficiency to neuroinflammation in AD also exists. By promoting proinflammatory responses, suppressing anti-inflammatory responses and impairing Aβ degradation and clearance, LC degeneration and NE loss can be considered a triple threat to AD pathogenesis. Remarkably, restoration of NE reverses these effects and slows neurodegeneration in animal models, raising the possibility that treatments which increase NE transmission may have the potential to delay or reverse AD-related pathology. This review describes the evidence supporting a key role for noradrenergic-based therapies to slow or prevent progressive neurodegeneration in AD. Specifically, since MCI coincides with the onset of clinical symptoms and brain atrophy, and LC pathology is already present at this early stage of AD pathogenesis, MCI may offer a critical window of time to initiate novel noradrenergic-based therapies aimed at the secondary wave of events that lead to progressive neurodegeneration. Because of the widespread clinical use of drugs with a NE-based mechanism of action, there are immediate opportunities to repurpose existing medications. For example, NE transport inhibitors and NE-precursor therapies that are used for treatment of neurologic and psychiatric disorders have shown promise in animal models of AD, and are now prime candidates for early-phase clinical trials in humans.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3706916}{PMC3706916}] [DOI:\href{http://dx.doi.org/10.1186/alzrt175}{10.1186/alzrt175}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/23634965}{23634965}] }
}
@article{pmid23622690,
  author = {Mattsson, N.  and Andreasson, U.  and Persson, S.  and Carrillo, M. C.  and Collins, S.  and Chalbot, S.  and Cutler, N.  and Dufour-Rainfray, D.  and Fagan, A. M.  and Heegaard, N. H.  and Robin Hsiung, G. Y.  and Hyman, B.  and Iqbal, K.  and Lachno, D. R.  and Lleo, A.  and Lewczuk, P.  and Molinuevo, J. L.  and Parchi, P.  and Regeniter, A.  and Rissman, R.  and Rosenmann, H.  and Sancesario, G.  and Schroder, J.  and Shaw, L. M.  and Teunissen, C. E.  and Trojanowski, J. Q.  and Vanderstichele, H.  and Vandijck, M.  and Verbeek, M. M.  and Zetterberg, H.  and Blennow, K.  and Kaser, S. A.  and Andreasson, U.  and Persson, S.  and Arai, H.  and Batish, S. D.  and Bernardini, S.  and Bocchio-Chiavetto, L.  and Blankenstein, M. A.  and Carrillo, M. C.  and Chalbot, S.  and Coart, E.  and Chiasserini, D.  and Cutler, N.  and Dahlfors, G.  and Duller, S.  and Fagan, A. M.  and Forlenza, O.  and Frisoni, G. B.  and Galasko, D.  and Galimberti, D.  and Hampel, H.  and Handberg, A.  and Heneka, M. T.  and Herskovits, A. Z.  and Herukka, S. K.  and Holtzman, D. M.  and Humpel, C.  and Hyman, B. T.  and Iqbal, K.  and Jukcer, M.  and Kaeser, S. A.  and Kaiser, E.  and Kapaki, E.  and Kidd, D.  and Klivenyi, P.  and Knudsen, C. S.  and Kummer, M. P.  and Lui, J.  and Llado, A.  and Lewezuk, P.  and Li, Q. X.  and Martins, R.  and Masters, C.  and McAuliffe, J.  and Mercken, M.  and Moghekar, A.  and Molinuevo, J. L.  and Montine, T. J.  and Nowatzke, W.  and O'Brien, R.  and Otto, M.  and Paraskevas, G. P.  and Parnetti, L.  and Petersen, R. C.  and Prvulovic, D.  and de Reus, H. P.  and Rissman, R. A.  and Scarpini, E.  and Stefani, A.  and Soininen, H.  and Schroder, J.  and Shaw, L. M.  and Skinningsrud, A.  and Skrogstad, B.  and Spreer, A.  and Talib, L.  and Teunissen, C.  and Trojanowski, J. Q.  and Tumani, H.  and Umek, R. M.  and Van Broeck, B.  and Vanderstichele, H.  and Vecsei, L.  and Verbeek, M. M.  and Windisch, M.  and Zhang, J.  and Zetterberg, H.  and Blennow, K. },
  title = {{C}{S}{F} biomarker variability in the {A}lzheimer's {A}ssociation quality control program},
  journal = {Alzheimers Dement},
  year = {2013},
  volume = {9},
  number = {3},
  pages = {251--261},
  month = {May},
  abstract = {The cerebrospinal fluid (CSF) biomarkers amyloid beta 1-42, total tau, and phosphorylated tau are used increasingly for Alzheimer's disease (AD) research and patient management. However, there are large variations in biomarker measurements among and within laboratories.\\ Data from the first nine rounds of the Alzheimer's Association quality control program was used to define the extent and sources of analytical variability. In each round, three CSF samples prepared at the Clinical Neurochemistry Laboratory (Mölndal, Sweden) were analyzed by single-analyte enzyme-linked immunosorbent assay (ELISA), a multiplexing xMAP assay, or an immunoassay with electrochemoluminescence detection.\\ A total of 84 laboratories participated. Coefficients of variation (CVs) between laboratories were around 20\% to 30\%; within-run CVs, less than 5\% to 10\%; and longitudinal within-laboratory CVs, 5\% to 19\%. Interestingly, longitudinal within-laboratory CV differed between biomarkers at individual laboratories, suggesting that a component of it was assay dependent. Variability between kit lots and between laboratories both had a major influence on amyloid beta 1-42 measurements, but for total tau and phosphorylated tau, between-kit lot effects were much less than between-laboratory effects. Despite the measurement variability, the between-laboratory consistency in classification of samples (using prehoc-derived cutoffs for AD) was high (>90\% in 15 of 18 samples for ELISA and in 12 of 18 samples for xMAP).\\ The overall variability remains too high to allow assignment of universal biomarker cutoff values for a specific intended use. Each laboratory must ensure longitudinal stability in its measurements and use internally qualified cutoff levels. Further standardization of laboratory procedures and improvement of kit performance will likely increase the usefulness of CSF AD biomarkers for researchers and clinicians.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3707386}{PMC3707386}] [DOI:\href{http://dx.doi.org/10.1016/j.jalz.2013.01.010}{10.1016/j.jalz.2013.01.010}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/23622690}{23622690}] }
}
@article{pmid23524657,
  author = {Molinuevo, J. L.  and Gispert, J. D.  and Dubois, B.  and Heneka, M. T.  and Lleo, A.  and Engelborghs, S.  and Pujol, J.  and de Souza, L. C.  and Alcolea, D.  and Jessen, F.  and Sarazin, M.  and Lamari, F.  and Balasa, M.  and Antonell, A.  and Rami, L. },
  title = {{T}he {A}{D}-{C}{S}{F}-index discriminates {A}lzheimer's disease patients from healthy controls: a validation study},
  journal = {J. Alzheimers Dis.},
  year = {2013},
  volume = {36},
  number = {1},
  pages = {67--77},
  abstract = {Cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) show an acceptable diagnostic sensitivity and specificity; however, their interpretation and ease of use is far from optimal.\\ To study and validate the diagnostic accuracy of an easy-to-use normalized CSF biomarker index, the AD-CSF-index, in different European populations.\\ A total of 342 subjects, 103 healthy controls and 239 AD patients, from four European memory clinics were included. The AD-CSF-index was constructed from the addition of normalized values between the minimum and maximum of amyloid and tau protein levels. The diagnostic accuracy, receiver operating characteristic, and regression analysis of the AD-CSF-index and other composite indices were evaluated in this study.\\ AD patients presented a significantly higher AD-CSF-index than healthy subjects (control = 0.5204; AD = 1.2272; p < 0.001). The AD-CSF-index obtained a sensitivity of 88.6\% at 85\% specificity and also showed a significantly higher diagnostic power (p < 0.05) than the individual CSF biomarkers and other studied indices. The performance of the AD-CSF-index was very similar between ELISA and MesoScale measurements. Cut-off values of approximately 0.75 provided the lowest achievable overall classification errors and a cut-off point of about 0.95 consistently provided specificities above 85\%.\\ The AD-CSF-index represents a novel approach, combining normalized CSF values, for the biological diagnosis of AD. The AD-CSF-index presents an optimal AUC with high sensitivity and specificity and seems to be a simple and intuitive way to interpret AD CSF biomarker results even from different analytical platforms.},
  note = {[DOI:\href{http://dx.doi.org/10.3233/JAD-130203}{10.3233/JAD-130203}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/23524657}{23524657}] }
}
@article{pmid23468966,
  author = {Zimmermann, J.  and Krauthausen, M.  and Hofer, M. J.  and Heneka, M. T.  and Campbell, I. L.  and Muller, M. },
  title = {{C}{N}{S}-targeted production of {I}{L}-17{A} induces glial activation, microvascular pathology and enhances the neuroinflammatory response to systemic endotoxemia},
  journal = {PLoS ONE},
  year = {2013},
  volume = {8},
  number = {2},
  pages = {e57307},
  abstract = {Interleukin-17A (IL-17A) is a key cytokine modulating the course of inflammatory diseases. Whereas effector functions of IL-17A like induction of antimicrobial peptides and leukocyte infiltration could clearly be demonstrated for peripheral organs, CNS specific effects are not well defined and appear controversial. To further clarify the functional significance of IL-17A in the CNS, we generated a transgenic mouse line with astrocyte-restricted expression of the IL-17A gene. GFAP/IL-17A transgenic mice develop normally and do not show any signs of neurological dysfunction. However, histological characterization revealed astrocytosis and activation of microglia. Demyelination, neurodegeneration or prominent tissue damage was not observed but a vascular pathology mimicking microangiopathic features was evident. Histological and flow cytometric analysis demonstrated the absence of parenchymal infiltration of immune cells into the CNS of GFAP/IL-17A transgenic mice. In GFAP/IL-17A mice, LPS-induced endotoxemia led to a more pronounced microglial activation with expansion of a distinct CD45(high)/CD11b(+) population and increased induction of proinflammatory cytokines compared with controls. Our data argues against a direct role of IL-17A in mediating tissue damage during neuroinflammation. More likely IL-17A acts as a modulating factor in the network of induced cytokines. This novel mouse model will be a very useful tool to further characterize the role of IL-17A in neuroinflammatory disease models.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3584143}{PMC3584143}] [DOI:\href{http://dx.doi.org/10.1371/journal.pone.0057307}{10.1371/journal.pone.0057307}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/23468966}{23468966}] }
}
@article{pmid23393549,
  author = {Okroglic, S.  and Widmann, C. N.  and Urbach, H.  and Scheltens, P.  and Heneka, M. T. },
  title = {{C}linical symptoms and risk factors in cerebral microangiopathy patients},
  journal = {PLoS ONE},
  year = {2013},
  volume = {8},
  number = {2},
  pages = {e53455},
  abstract = {Although the clinical manifestation and risk factors of cerebral microangiopathy (CM) remain unclear, the number of diagnoses is increasing. Hence, patterns of association among lesion topography and severity, clinical symptoms and demographic and disease risk factors were investigated retrospectively in a cohort of CM patients.\\ Patients treated at the Department of Neurology, University of Bonn for CM (n = 223; 98m, 125f; aged 77.32±9.09) from 2005 to 2010 were retrospectively enrolled. Clinical symptoms, blood chemistry, potential risk factors, demographic data and ratings of vascular pathology in the brain based on the Wahlund scale were analyzed using Pearson's chi square test and one-way ANOVA.\\ Progressive cognitive decline (38.1\%), gait apraxia (27.8\%), stroke-related symptoms and seizures (24.2\%), TIA-symptoms (22\%) and vertigo (17\%) were frequent symptoms within the study population. Frontal lobe WMLs/lacunar infarcts led to more frequent presentation of progressive cognitive decline, seizures, gait apraxia, stroke-related symptoms, TIA, vertigo and incontinence. Parietooccipital WMLs/lacunar infarcts were related to higher frequencies of TIA, seizures and incontinence. Basal ganglia WMLs/lacunar infarcts were seen in patients with more complaints of gait apraxia, vertigo and incontinence. Age (p = .012), arterial hypertension (p<.000), obesity (p<.000) and cerebral macroangiopathy (p = .018) were positively related to cerebral lesion load. For increased glucose level, homocysteine, CRP and D-Dimers there was no association.\\ This underlines the association of CM with neurological symptoms upon admission in a topographical manner. Seizures and vertigo are symptoms of CM which may have been missed in previous studies. In addition to confirming known risk factors such as aging and arterial hypertension, obesity appears to increase the risk as well. Since the incidence of CM is increasing, future studies should focus on the importance of prevention of vascular risk factors on its pathogenesis.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3564848}{PMC3564848}] [DOI:\href{http://dx.doi.org/10.1371/journal.pone.0053455}{10.1371/journal.pone.0053455}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/23393549}{23393549}] }
}
@article{pmid23254930,
  author = {Heneka, M. T.  and Kummer, M. P.  and Stutz, A.  and Delekate, A.  and Schwartz, S.  and Vieira-Saecker, A.  and Griep, A.  and Axt, D.  and Remus, A.  and Tzeng, T. C.  and Gelpi, E.  and Halle, A.  and Korte, M.  and Latz, E.  and Golenbock, D. T. },
  title = {{N}{L}{R}{P}3 is activated in {A}lzheimer's disease and contributes to pathology in {A}{P}{P}/{P}{S}1 mice},
  journal = {Nature},
  year = {2013},
  volume = {493},
  number = {7434},
  pages = {674--678},
  month = {Jan},
  abstract = {Alzheimer's disease is the world's most common dementing illness. Deposition of amyloid-β peptide drives cerebral neuroinflammation by activating microglia. Indeed, amyloid-β activation of the NLRP3 inflammasome in microglia is fundamental for interleukin-1β maturation and subsequent inflammatory events. However, it remains unknown whether NLRP3 activation contributes to Alzheimer's disease in vivo. Here we demonstrate strongly enhanced active caspase-1 expression in human mild cognitive impairment and brains with Alzheimer's disease, suggesting a role for the inflammasome in this neurodegenerative disease. Nlrp3(-/-) or Casp1(-/-) mice carrying mutations associated with familial Alzheimer's disease were largely protected from loss of spatial memory and other sequelae associated with Alzheimer's disease, and demonstrated reduced brain caspase-1 and interleukin-1β activation as well as enhanced amyloid-β clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells to an M2 phenotype and resulted in the decreased deposition of amyloid-β in the APP/PS1 model of Alzheimer's disease. These results show an important role for the NLRP3/caspase-1 axis in the pathogenesis of Alzheimer's disease, and suggest that NLRP3 inflammasome inhibition represents a new therapeutic intervention for the disease.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3812809}{PMC3812809}] [DOI:\href{http://dx.doi.org/10.1038/nature11729}{10.1038/nature11729}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/23254930}{23254930}] }
}
@article{pmid23223301,
  author = {Kummer, M. P.  and Vogl, T.  and Axt, D.  and Griep, A.  and Vieira-Saecker, A.  and Jessen, F.  and Gelpi, E.  and Roth, J.  and Heneka, M. T. },
  title = {{M}rp14 deficiency ameliorates amyloid β burden by increasing microglial phagocytosis and modulation of amyloid precursor protein processing},
  journal = {J. Neurosci.},
  year = {2012},
  volume = {32},
  number = {49},
  pages = {17824--17829},
  month = {Dec},
  abstract = {Neuroinflammation plays a fundamental role in the pathogenesis of Alzheimer's disease (AD), resulting in the extensive activation of microglial and astroglial cells. Here we describe the role of myeloid-related protein Mrp14, a recently described amplifier of inflammation, in Alzheimer's disease and in the related amyloid precursor protein/presenilin1 (APP/PS1) mouse model. Detection of Mrp14 in control, mildly cognitive impaired, and AD patients revealed a strong induction of Mrp14 in protein extracts as well as in the cerebrospinal fluid, but not in blood plasma. In APP/PS1 mice, Mrp14 and its heterodimeric partner Mrp8 was found to be upregulated in microglial cells surrounding amyloid plaques. Functionally, loss of Mrp14 led to increased phagocytosis of fibrillar amyloid β (Aβ) in microglia cells in vitro and in vivo. Generating APP/PS1-transgenic mice deficient for Mrp14, we observed a decrease of key cytokines involved in APP processing, a reduction of BACE1 expression and activity, and consequently overall Aβ deposition. We therefore conclude that Mrp14 promotes APP processing and Aβ accumulation under neuroinflammatory conditions.},
  note = {[DOI:\href{http://dx.doi.org/10.1523/JNEUROSCI.1504-12.2012}{10.1523/JNEUROSCI.1504-12.2012}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/23223301}{23223301}] }
}
@article{pmid23197723,
  author = {Yamanaka, M.  and Ishikawa, T.  and Griep, A.  and Axt, D.  and Kummer, M. P.  and Heneka, M. T. },
  title = {{P}{P}{A}{R}γ/{R}{X}{R}α-induced and {C}{D}36-mediated microglial amyloid-β phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice},
  journal = {J. Neurosci.},
  year = {2012},
  volume = {32},
  number = {48},
  pages = {17321--17331},
  month = {Nov},
  abstract = {Alzheimer's disease (AD) is characterized by the extracellular deposition of amyloid-β (Aβ), neurofibrillary tangle formation, and a microglial-driven inflammatory response. Chronic inflammatory activation compromises microglial clearance functions. Because peroxisome proliferator-activated receptor γ (PPARγ) agonists suppress inflammatory gene expression, we tested whether activation of PPARγ would also result in improved microglial Aβ phagocytosis. The PPARγ agonist pioglitazone and a novel selective PPARα/γ modulator, DSP-8658, currently in clinical development for the treatment of type 2 diabetes, enhanced the microglial uptake of Aβ in a PPARγ-dependent manner. This PPARγ-stimulated increase of Aβ phagocytosis was mediated by the upregulation of scavenger receptor CD36 expression. In addition, combined treatment with agonists for the heterodimeric binding partners of PPARγ, the retinoid X receptors (RXRs), showed additive enhancement of the Aβ uptake that was mediated by RXRα activation. Evaluation of DSP-8658 in the amyloid precursor protein/presenilin 1 mouse model confirmed an increased microglial Aβ phagocytosis in vivo, which subsequently resulted in a reduction of cortical and hippocampal Aβ levels. Furthermore, DSP-8658-treated mice showed improved spatial memory performance. Therefore, stimulation of microglial clearance by simultaneous activation of the PPARγ/RXRα heterodimer may prove beneficial in prevention of AD.},
  note = {[DOI:\href{http://dx.doi.org/10.1523/JNEUROSCI.1569-12.2012}{10.1523/JNEUROSCI.1569-12.2012}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/23197723}{23197723}] }
}
@article{pmid23134661,
  author = {Semmler, A.  and Widmann, C. N.  and Okulla, T.  and Urbach, H.  and Kaiser, M.  and Widman, G.  and Mormann, F.  and Weide, J.  and Fliessbach, K.  and Hoeft, A.  and Jessen, F.  and Putensen, C.  and Heneka, M. T. },
  title = {{P}ersistent cognitive impairment, hippocampal atrophy and {E}{E}{G} changes in sepsis survivors},
  journal = {J. Neurol. Neurosurg. Psychiatr.},
  year = {2013},
  volume = {84},
  number = {1},
  pages = {62--69},
  month = {Jan},
  abstract = {The objective of this preliminary study was to explore long-term changes in neurobehavioral parameters, brain morphology and electroencephalography of sepsis patients who received intensive care compared to non-septic intensive care unit (ICU) patients.\\ Two-centre follow-up study 6-24 months after discharge from hospital using published norms and existing databases of healthy controls for comparison. Patients included 25 septic and 19 non-septic ICU survivors who were recruited from two ICUs of a university and community hospital. Measurements used include brain morphology, standard electroencephalography, cognition and psychiatric health and health-related quality of life.\\ Sepsis survivors showed cognitive deficits in verbal learning and memory and had a significant reduction of left hippocampal volume compared to healthy controls. Moreover, sepsis and to some extent non-septic ICU patients had more low-frequency activity in the EEG indicating unspecific brain dysfunction. No differences were found in health-related quality of life, psychological functioning or depressive symptoms, and depression could be ruled out as a confounding factor.\\ This study demonstrates permanent cognitive impairment in several domains in both septic and non-septic ICU survivors and unspecific brain dysfunction. In the sepsis group, left-sided hippocampal atrophy was found compared to healthy controls. Further study is needed to clarify what contribution sepsis and other factors at the ICU make to these outcomes. Specific neuroprotective therapies are warranted to prevent persisting brain changes in ICU patients.},
  note = {[DOI:\href{http://dx.doi.org/10.1136/jnnp-2012-302883}{10.1136/jnnp-2012-302883}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/23134661}{23134661}] }
}
@article{pmid23111906,
  author = {van der Zee, J.  and Gijselinck, I.  and Dillen, L.  and Van Langenhove, T.  and Theuns, J.  and Engelborghs, S.  and Philtjens, S.  and Vandenbulcke, M.  and Sleegers, K.  and Sieben, A.  and Baumer, V.  and Maes, G.  and Corsmit, E.  and Borroni, B.  and Padovani, A.  and Archetti, S.  and Perneczky, R.  and Diehl-Schmid, J.  and de Mendonca, A.  and Miltenberger-Miltenyi, G.  and Pereira, S.  and Pimentel, J.  and Nacmias, B.  and Bagnoli, S.  and Sorbi, S.  and Graff, C.  and Chiang, H. H.  and Westerlund, M.  and Sanchez-Valle, R.  and Llado, A.  and Gelpi, E.  and Santana, I.  and Almeida, M. R.  and Santiago, B.  and Frisoni, G.  and Zanetti, O.  and Bonvicini, C.  and Synofzik, M.  and Maetzler, W.  and Vom Hagen, J. M.  and Schols, L.  and Heneka, M. T.  and Jessen, F.  and Matej, R.  and Parobkova, E.  and Kovacs, G. G.  and Strobel, T.  and Sarafov, S.  and Tournev, I.  and Jordanova, A.  and Danek, A.  and Arzberger, T.  and Fabrizi, G. M.  and Testi, S.  and Salmon, E.  and Santens, P.  and Martin, J. J.  and Cras, P.  and Vandenberghe, R.  and De Deyn, P. P.  and Cruts, M.  and Van Broeckhoven, C.  and van der Zee, J.  and Gijselinck, I.  and Dillen, L.  and Van Langenhove, T.  and Theuns, J.  and Philtjens, S.  and Sleegers, K.  and Baumer, V.  and Maes, G.  and Corsmit, E.  and Cruts, M.  and Van Broeckhoven, C.  and van der Zee, J.  and Gijselinck, I.  and Dillen, L.  and Van Langenhove, T.  and Philtjens, S.  and Theuns, J.  and Sleegers, K.  and Baumer, V.  and Maes, G.  and Cruts, M.  and Van Broeckhoven, C.  and Engelborghs, S.  and De Deyn, P. P.  and Cras, P.  and Engelborghs, S.  and De Deyn, P. P.  and Vandenbulcke, M.  and Vandenbulcke, M.  and Borroni, B.  and Padovani, A.  and Archetti, S.  and Perneczky, R.  and Diehl-Schmid, J.  and Synofzik, M.  and Maetzler, W.  and Muller Vom Hagen, J.  and Schols, L.  and Synofzik, M.  and Maetzler, W.  and Muller Vom Hagen, J.  and Schols, L.  and Heneka, M. T.  and Jessen, F.  and Ramirez, A.  and Kurzwelly, D.  and Sachtleben, C.  and Mairer, W.  and de Mendonca, A.  and Miltenberger-Miltenyi, G.  and Pereira, S.  and Firmo, C.  and Pimentel, J.  and Sanchez-Valle, R.  and Llado, A.  and Antonell, A.  and Molinuevo, J.  and Gelpi, E.  and Graff, C.  and Chiang, H. H.  and Westerlund, M.  and Graff, C.  and Kinhult Stahlbom, A.  and Thonberg, H.  and Nennesmo, I.  and Borjesson-Hanson, A.  and Nacmias, B.  and Bagnoli, S.  and Sorbi, S.  and Bessi, V.  and Piaceri, I.  and Santana, I.  and Santiago, B.  and Santana, I.  and Helena Ribeiro, M.  and Rosario Almeida, M.  and Oliveira, C.  and Massano, J.  and Garret, C.  and Pires, P.  and Frisoni, G.  and Zanetti, O.  and Bonvicini, C.  and Sarafov, S.  and Tournev, I.  and Jordanova, A.  and Tournev, I.  and Kovacs, G. G.  and Strobel, T.  and Heneka, M. T.  and Jessen, F.  and Ramirez, A.  and Kurzwelly, D.  and Sachtleben, C.  and Mairer, W.  and Jessen, F.  and Matej, R.  and Parobkova, E.  and Danel, A.  and Arzberger, T.  and Maria Fabrizi, G.  and Testi, S.  and Ferrari, S.  and Cavallaro, T.  and Salmon, E.  and Santens, P.  and Cras, P. },
  title = {{A} pan-{E}uropean study of the {C}9orf72 repeat associated with {F}{T}{L}{D}: geographic prevalence, genomic instability, and intermediate repeats},
  journal = {Hum. Mutat.},
  year = {2013},
  volume = {34},
  number = {2},
  pages = {363--373},
  month = {Feb},
  abstract = {We assessed the geographical distribution of C9orf72 G(4) C(2) expansions in a pan-European frontotemporal lobar degeneration (FTLD) cohort (n = 1,205), ascertained by the European Early-Onset Dementia (EOD) consortium. Next, we performed a meta-analysis of our data and that of other European studies, together 2,668 patients from 15 Western European countries. The frequency of the C9orf72 expansions in Western Europe was 9.98\% in overall FTLD, with 18.52\% in familial, and 6.26\% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of respectively 29.33\% and 20.73\%, but also Spain with 25.49\%. In contrast, prevalence in Germany was limited to 4.82\%. In addition, we studied the role of intermediate repeats (7-24 repeat units), which are strongly correlated with the risk haplotype, on disease and C9orf72 expression. In vitro reporter gene expression studies demonstrated significantly decreased transcriptional activity of C9orf72 with increasing number of normal repeat units, indicating that intermediate repeats might act as predisposing alleles and in favor of the loss-of-function disease mechanism. Further, we observed a significantly increased frequency of short indels in the GC-rich low complexity sequence adjacent to the G(4) C(2) repeat in C9orf72 expansion carriers (P < 0.001) with the most common indel creating one long contiguous imperfect G(4) C(2) repeat, which is likely more prone to replication slippage and pathological expansion.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3638346}{PMC3638346}] [DOI:\href{http://dx.doi.org/10.1002/humu.22244}{10.1002/humu.22244}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/23111906}{23111906}] }
}
@article{pmid22914828,
  author = {Scheef, L.  and Spottke, A.  and Daerr, M.  and Joe, A.  and Striepens, N.  and Kolsch, H.  and Popp, J.  and Daamen, M.  and Gorris, D.  and Heneka, M. T.  and Boecker, H.  and Biersack, H. J.  and Maier, W.  and Schild, H. H.  and Wagner, M.  and Jessen, F. },
  title = {{G}lucose metabolism, gray matter structure, and memory decline in subjective memory impairment},
  journal = {Neurology},
  year = {2012},
  volume = {79},
  number = {13},
  pages = {1332--1339},
  month = {Sep},
  abstract = {To identify biological evidence for Alzheimer disease (AD) in individuals with subjective memory impairment (SMI) and unimpaired cognitive performance and to investigate the longitudinal cognitive course in these subjects.\\ [¹⁸F]fluoro-2-deoxyglucose PET (FDG-PET) and structural MRI were acquired in 31 subjects with SMI and 56 controls. Cognitive follow-up testing was performed (average follow-up time: 35 months). Differences in baseline brain imaging data and in memory decline were assessed between both groups. Associations of memory decline with brain imaging data were tested.\\ The SMI group showed hypometabolism in the right precuneus and hypermetabolism in the right medial temporal lobe. Gray matter volume was reduced in the right hippocampus in the SMI group. At follow-up, subjects with SMI showed a poorer performance than controls on measures of episodic memory. Longitudinal memory decline in the SMI group was associated with reduced glucose metabolism in the right precuneus at baseline.\\ The cross-sectional difference in 2 independent neuroimaging modalities indicates early AD pathology in SMI. The poorer memory performance at follow-up and the association of reduced longitudinal memory performance with hypometabolism in the precuneus at baseline support the concept of SMI as the earliest manifestation of AD.},
  note = {[DOI:\href{http://dx.doi.org/10.1212/WNL.0b013e31826c1a8d}{10.1212/WNL.0b013e31826c1a8d}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/22914828}{22914828}] }
}
@article{pmid22883210,
  author = {Hammerschmidt, T.  and Kummer, M. P.  and Terwel, D.  and Martinez, A.  and Gorji, A.  and Pape, H. C.  and Rommelfanger, K. S.  and Schroeder, J. P.  and Stoll, M.  and Schultze, J.  and Weinshenker, D.  and Heneka, M. T. },
  title = {{S}elective loss of noradrenaline exacerbates early cognitive dysfunction and synaptic deficits in {A}{P}{P}/{P}{S}1 mice},
  journal = {Biol. Psychiatry},
  year = {2013},
  volume = {73},
  number = {5},
  pages = {454--463},
  month = {Mar},
  abstract = {Degeneration of the locus coeruleus (LC), the major noradrenergic nucleus in the brain, occurs early and is ubiquitous in Alzheimer's disease (AD). Experimental lesions to the LC exacerbate AD-like neuropathology and cognitive deficits in several transgenic mouse models of AD. Because the LC contains multiple neuromodulators known to affect amyloid β toxicity and cognitive function, the specific role of noradrenaline (NA) in AD is not well understood.\\ To determine the consequences of selective NA deficiency in an AD mouse model, we crossed dopamine β-hydroxylase (DBH) knockout mice with amyloid precursor protein (APP)/presenilin-1 (PS1) mice overexpressing mutant APP and PS1. Dopamine β-hydroxylase (-/-) mice are unable to synthesize NA but otherwise have normal LC neurons and co-transmitters. Spatial memory, hippocampal long-term potentiation, and synaptic protein levels were assessed.\\ The modest impairments in spatial memory and hippocampal long-term potentiation displayed by young APP/PS1 or DBH (-/-) single mutant mice were augmented in DBH (-/-)/APP/PS1 double mutant mice. Deficits were associated with reduced levels of total calcium/calmodulin-dependent protein kinase II and N-methyl-D-aspartate receptor 2A and increased N-methyl-D-aspartate receptor 2B levels and were independent of amyloid β accumulation. Spatial memory performance was partly improved by treatment with the NA precursor drug L-threo-dihydroxyphenylserine.\\ These results indicate that early LC degeneration and subsequent NA deficiency in AD may contribute to cognitive deficits via altered levels of calcium/calmodulin-dependent protein kinase II and N-methyl-D-aspartate receptors and suggest that NA supplementation could be beneficial in early AD.},
  note = {[DOI:\href{http://dx.doi.org/10.1016/j.biopsych.2012.06.013}{10.1016/j.biopsych.2012.06.013}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/22883210}{22883210}] }
}
@article{pmid22820684,
  author = {Semmler, A.  and Okulla, T.  and Kaiser, M.  and Seifert, B.  and Heneka, M. T. },
  title = {{L}ong-term neuromuscular sequelae of critical illness},
  journal = {J. Neurol.},
  year = {2013},
  volume = {260},
  number = {1},
  pages = {151--157},
  month = {Jan},
  abstract = {In this observational study, we analyzed the long-term neuromuscular deficits of survivors of critical illness. Intensive care unit-acquired muscular weakness (ICU-AW) is a very common complication of critical illness. Critical illness polyneuropathy (CIP) and critical illness myopathy (CIM) are two main contributors to ICU-AW. ICU-AW is associated with an increased mortality and leads to rehabilitation problems. However, the long-term outcome of ICU-AW and factors influencing it are not well known. We analyzed the medical records of 490 survivors of critical illness, aged 18-75 years and located in the area of the study center. Intensive care unit (ICU) survivors with comorbidities that might influence neuromuscular follow-up examinations, muscle strength, or results of nerve conduction studies, such as renal or hepatic insufficiency, diabetes mellitus, or vitamin deficiency were excluded. A total of 51 patients were finally included in the study. Six to 24 months after discharge from the ICU, we measured the Medical Research Council (MRC) sum score, the Overall Disability Sum score (ODSS), and also performed nerve conduction studies and EMG. For all ICU survivors, the median MRC sum score was 60 (range 47-60) and the median ODSS score was 0 (range 0-8). CIP was diagnosed in 21 patients (41 \%). No patient was diagnosed with CIM. Patients with diagnosis of CIP showed a higher median ODSS scores 1 (range 0-8) versus 0 (range 0-5); p < 0.001 and lower median MRC sum scores 56 (range 47-60) versus 60 (range 58-60); p < 0.001. The three main outcome variables MRC sum score, ODSS score and diagnosis of CIP were not related to age, gender, or diagnosis of sepsis. The MRC sum score (r = -0.33; p = 0.02) and the ODSS score (r = 0.31; p = 0.029) were correlated with the APACHE score. There was a trend for an increased APACHE score in patients with diagnosis of CIP 19 (range 6-33) versus 16.5 (range 6-28); p = 0.065. Patients with the diagnosis of CIP had more days of ICU treatment 11 days (range 2-74) versus 4 days (range 1-61); p = 0.015, and had more days of ventilator support 8 days (range 1-59) versus 2 days (range 1-46); p = 0.006. The MRC sum score and the ODSS score were correlated with the days of ICU treatment and with the days of ventilator support. The neuromuscular long-term consequences of critical illness were not severe in our study population. As patients with concomitant diseases and old patients were excluded from this study the result of an overall favorable prognosis of ICU-acquired weakness may not be true for other patient's case-mix. Risk factors for the development of long-term critical illness neuropathy are duration of ICU treatment, duration of ventilator support, and a high APACHE score, but not diagnosis of sepsis. Although ICU-AW can be serious complication of ICU treatment, this should not influence therapeutic decisions, given its favorable long-term prognosis, at least in relatively young patients with no concomitant diseases.},
  note = {[DOI:\href{http://dx.doi.org/10.1007/s00415-012-6605-4}{10.1007/s00415-012-6605-4}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/22820684}{22820684}] }
}
@article{pmid22715372,
  author = {Dupuis, L.  and Dengler, R.  and Heneka, M. T.  and Meyer, T.  and Zierz, S.  and Kassubek, J.  and Fischer, W.  and Steiner, F.  and Lindauer, E.  and Otto, M.  and Dreyhaupt, J.  and Grehl, T.  and Hermann, A.  and Winkler, A. S.  and Bogdahn, U.  and Benecke, R.  and Schrank, B.  and Wessig, C.  and Grosskreutz, J.  and Ludolph, A. C.  and Borisow, N.  and Holm, T.  and Maier, A.  and Meyer, T.  and Budde, P.  and Grehl, T.  and Guettsches, A. K.  and Bewersdorff, M.  and Heneka, M.  and Hermann, A.  and Storch, A.  and Frank, T.  and Goricke, B.  and Weishaupt, J.  and Eger, K.  and Hanisch, F.  and Zierz, S.  and Cordes, A. L.  and Dengler, R.  and Koerner, S.  and Kollewe, K.  and Petri, S.  and Grosskreutz, J.  and Kunze, A.  and Prell, T.  and Ringer, T.  and Zinke, J.  and Anneser, J.  and Borasio, G. D.  and Chahli, C.  and Winkler, A. S.  and Boentert, M.  and Stubbe-Draeger, B.  and Young, P.  and Bogdahn, U.  and Franz, S.  and Haringer, V.  and Weidner, N.  and Benecke, R.  and Meister, S.  and Prudlo, J.  and Wittstock, M.  and Dorst, J.  and Hendrich, C.  and Ludolph, A. C.  and Sperfeld, A. D.  and Weiland, U.  and Neidhardt, S.  and Schrank, B.  and Beck, M.  and Kraft, P.  and Toyka, K.  and Ulzheimer, J.  and Wessig, C. },
  title = {{A} randomized, double blind, placebo-controlled trial of pioglitazone in combination with riluzole in amyotrophic lateral sclerosis},
  journal = {PLoS ONE},
  year = {2012},
  volume = {7},
  number = {6},
  pages = {e37885},
  abstract = {Pioglitazone, an oral anti-diabetic that stimulates the PPAR-gamma transcription factor, increased survival of mice with amyotrophic lateral sclerosis (ALS).\\ We performed a phase II, double blind, multicentre, placebo controlled trial of pioglitazone in ALS patients under riluzole. 219 patients were randomly assigned to receive 45 mg/day of pioglitazone or placebo (one: one allocation ratio). The primary endpoint was survival. Secondary endpoints included incidence of non-invasive ventilation and tracheotomy, and slopes of ALS-FRS, slow vital capacity, and quality of life as assessed using EUROQoL EQ-5D. The study was conducted under a two-stage group sequential test, allowing to stop for futility or superiority after interim analysis. Shortly after interim analysis, 30 patients under pioglitazone and 24 patients under placebo had died. The trial was stopped for futility; the hazard ratio for primary endpoint was 1.21 (95\% CI: 0.71-2.07, p = 0.48). Secondary endpoints were not modified by pioglitazone treatment. Pioglitazone was well tolerated.\\ Pioglitazone has no beneficial effects on the survival of ALS patients as add-on therapy to riluzole.\\ Clinicaltrials.gov NCT00690118.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3371007}{PMC3371007}] [DOI:\href{http://dx.doi.org/10.1371/journal.pone.0037885}{10.1371/journal.pone.0037885}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/22715372}{22715372}] }
}
@article{pmid22654722,
  author = {Heneka, M. T.  and Reyes-Irisarri, E.  and Hull, M.  and Kummer, M. P. },
  title = {{I}mpact and {T}herapeutic {P}otential of {P}{P}{A}{R}s in {A}lzheimer's {D}isease},
  journal = {Curr Neuropharmacol},
  year = {2011},
  volume = {9},
  number = {4},
  pages = {643--650},
  month = {Dec},
  abstract = {Peroxisome proliferator activated receptors (PPARs) are well studied for their role of peripheral metabolism, but they also may be involved in the pathogenesis of various disorders of the central nervous system (CNS) including multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's and, Parkinson's disease. The observation that PPARs are able to suppress the inflammatory response in peripheral macrophages and in several models of human autoimmune diseases, lead to the idea that PPARs might be beneficial for CNS disorders possessing an inflammatory component. The neuroinflammatory response during the course of Alzheimer's disease (AD) is triggered by the deposition of the β-amyloid peptide in extracellular plaques and ongoing neurodegeneration. Non-steroidal anti-inflammatory drugs (NSAIDs) have been considered to delay the onset and reduce the risk to develop Alzheimer's disease, while they also directly activate PPARγ. This led to the hypothesis that NSAID protection in AD may be partly mediated by PPARγ. Several lines of evidence have supported this hypothesis, using AD related transgenic cellular and animal models. Stimulation of PPARγ by synthetic agonist (thiazolidinediones) inducing anti-inflammatory, anti-amyloidogenic and insulin sensitizing effects may account for the observed effects. Several clinical trials already revealed promising results using PPARγ agonists, therefore PPARγ represents an attractive therapeutic target for the treatment of AD.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3263458}{PMC3263458}] [DOI:\href{http://dx.doi.org/10.2174/157015911798376325}{10.2174/157015911798376325}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/22654722}{22654722}] }
}
@article{pmid22651996,
  author = {Rapic, S.  and Backes, H.  and Viel, T.  and Kummer, M. P.  and Monfared, P.  and Neumaier, B.  and Vollmar, S.  and Hoehn, M.  and Van der Linden, A.  and Heneka, M. T.  and Jacobs, A. H. },
  title = {{I}maging microglial activation and glucose consumption in a mouse model of {A}lzheimer's disease},
  journal = {Neurobiol. Aging},
  year = {2013},
  volume = {34},
  number = {1},
  pages = {351--354},
  month = {Jan},
  abstract = {In Alzheimer's disease (AD), persistent microglial activation as sign of chronic neuroinflammation contributes to disease progression. Our study aimed to in vivo visualize and quantify microglial activation in 13- to 15-month-old AD mice using [(11)C]-(R)-PK11195 and positron emission tomography (PET). We attempted to modulate neuroinflammation by subjecting the animals to an anti-inflammatory treatment with pioglitazone (5-weeks' treatment, 5-week wash-out period). [(11)C]-(R)-PK11195 distribution volume values in AD mice were significantly higher compared with control mice after the wash-out period at 15 months, which was supported by immunohistochemistry data. However, [(11)C]-(R)-PK11195 μPET could not demonstrate genotype- or treatment-dependent differences in the 13- to 14-month-old animals, suggesting that microglial activation in AD mice at this age and disease stage is too mild to be detected by this imaging method.},
  note = {[DOI:\href{http://dx.doi.org/10.1016/j.neurobiolaging.2012.04.016}{10.1016/j.neurobiolaging.2012.04.016}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/22651996}{22651996}] }
}
@article{pmid22549622,
  author = {Jacobs, A. H.  and Tavitian, B.  and Jacobs, A. H.  and Schaefers, M.  and Schober, O.  and Maggi, A.  and Vegeto, E.  and Aigner, L.  and Chalon, S.  and Vercouillie, J.  and Guilloteau, D.  and Camus, V.  and Aime, S.  and Terreno, E.  and Planas, A. M.  and Linden, A. V.  and Ponsaerts, P.  and Tavitian, B.  and Boisgard, R.  and Winkeler, A.  and Dolle, F.  and Lammertsma, A. A.  and Windhorst, A. D.  and Herholz, K.  and Gerhard, A.  and Boutin, H.  and Perani, D.  and Moresco, R. M.  and Halldin, C.  and Varrone, A.  and Nordberg, A.  and Van Laere, K.  and Bormans, G.  and Baekelandt, V.  and Knudsen, G. M.  and Pinborg, L. H.  and Pappata, S.  and Quarantelli, M.  and Rinne, J.  and Holmes, C.  and Brooks, D. J.  and Roncaroli, F.  and Turkheimer, F.  and Kassiou, M.  and Heneka, M. T.  and Ciana, P.  and Perk, L. R.  and Cyclotron, B. V.  and Cavallotti, C.  and Alavijeh, M.  and Mathe, D.  and R?nn, L. C.  and Str?b?k, D. },
  title = {{N}oninvasive molecular imaging of neuroinflammation},
  journal = {J. Cereb. Blood Flow Metab.},
  year = {2012},
  volume = {32},
  number = {7},
  pages = {1393--1415},
  month = {Jul},
  abstract = {Inflammation is a highly dynamic and complex adaptive process to preserve and restore tissue homeostasis. Originally viewed as an immune-privileged organ, the central nervous system (CNS) is now recognized to have a constant interplay with the innate and the adaptive immune systems, where resident microglia and infiltrating immune cells from the periphery have important roles. Common diseases of the CNS, such as stroke, multiple sclerosis (MS), and neurodegeneration, elicit a neuroinflammatory response with the goal to limit the extent of the disease and to support repair and regeneration. However, various disease mechanisms lead to neuroinflammation (NI) contributing to the disease process itself. Molecular imaging is the method of choice to try to decipher key aspects of the dynamic interplay of various inducers, sensors, transducers, and effectors of the orchestrated inflammatory response in vivo in animal models and patients. Here, we review the basic principles of NI with emphasis on microglia and common neurologic disease mechanisms, the molecular targets which are being used and explored for imaging, and molecular imaging of NI in frequent neurologic diseases, such as stroke, MS, neurodegeneration, epilepsy, encephalitis, and gliomas.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390799}{PMC3390799}] [DOI:\href{http://dx.doi.org/10.1038/jcbfm.2012.53}{10.1038/jcbfm.2012.53}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/22549622}{22549622}] }
}
@article{pmid22251135,
  author = {Parpura, V.  and Heneka, M. T.  and Montana, V.  and Oliet, S. H.  and Schousboe, A.  and Haydon, P. G.  and Stout, R. F.  and Spray, D. C.  and Reichenbach, A.  and Pannicke, T.  and Pekny, M.  and Pekna, M.  and Zorec, R.  and Verkhratsky, A. },
  title = {{G}lial cells in (patho)physiology},
  journal = {J. Neurochem.},
  year = {2012},
  volume = {121},
  number = {1},
  pages = {4--27},
  month = {Apr},
  abstract = {Neuroglial cells define brain homeostasis and mount defense against pathological insults. Astroglia regulate neurogenesis and development of brain circuits. In the adult brain, astrocytes enter into intimate dynamic relationship with neurons, especially at synaptic sites where they functionally form the tripartite synapse. At these sites, astrocytes regulate ion and neurotransmitter homeostasis, metabolically support neurons and monitor synaptic activity; one of the readouts of the latter manifests in astrocytic intracellular Ca(2+) signals. This form of astrocytic excitability can lead to release of chemical transmitters via Ca(2+) -dependent exocytosis. Once in the extracellular space, gliotransmitters can modulate synaptic plasticity and cause changes in behavior. Besides these physiological tasks, astrocytes are fundamental for progression and outcome of neurological diseases. In Alzheimer's disease, for example, astrocytes may contribute to the etiology of this disorder. Highly lethal glial-derived tumors use signaling trickery to coerce normal brain cells to assist tumor invasiveness. This review not only sheds new light on the brain operation in health and disease, but also points to many unknowns.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3304021}{PMC3304021}] [DOI:\href{http://dx.doi.org/10.1111/j.1471-4159.2012.07664.x}{10.1111/j.1471-4159.2012.07664.x}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/22251135}{22251135}] }
}
@article{pmid22227962,
  author = {Kummer, M. P.  and Hulsmann, C.  and Hermes, M.  and Axt, D.  and Heneka, M. T. },
  title = {{N}itric oxide decreases the enzymatic activity of insulin degrading enzyme in {A}{P}{P}/{P}{S}1 mice},
  journal = {J Neuroimmune Pharmacol},
  year = {2012},
  volume = {7},
  number = {1},
  pages = {165--172},
  month = {Mar},
  abstract = {Nitric oxide has been implicated in the regulation of enzyme activity, particularly the activity of metalloproteinases. Since the inducible form of the nitric oxide synthase (NOS2), is upregulated in Alzheimer's disease, we investigated the activity of two amyloid β degrading enzymes, IDE and neprilysin. In vitro we demonstrated that the activity of IDE was inhibited by *NO donor Sin-1, whereas activity of neprilysin remained unaffected. In vivo the activity of insulin-degrading enzyme was lowered in APP/PS1 mice, but not in APP/PS1/NOS2(-/-) mice. These data suggest that NOS2 upregulation impairs amyloid β degradation through negative regulation of IDE activity and thus loss of NOS2 activity will positively influence amyloid β clearance.},
  note = {[DOI:\href{http://dx.doi.org/10.1007/s11481-011-9339-7}{10.1007/s11481-011-9339-7}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/22227962}{22227962}] }
}
@article{pmid22198949,
  author = {Liu, S.  and Liu, Y.  and Hao, W.  and Wolf, L.  and Kiliaan, A. J.  and Penke, B.  and Rube, C. E.  and Walter, J.  and Heneka, M. T.  and Hartmann, T.  and Menger, M. D.  and Fassbender, K. },
  title = {{T}{L}{R}2 is a primary receptor for {A}lzheimer's amyloid β peptide to trigger neuroinflammatory activation},
  journal = {J. Immunol.},
  year = {2012},
  volume = {188},
  number = {3},
  pages = {1098--1107},
  month = {Feb},
  abstract = {Microglia activated by extracellularly deposited amyloid β peptide (Aβ) act as a two-edged sword in Alzheimer's disease pathogenesis: on the one hand, they damage neurons by releasing neurotoxic proinflammatory mediators (M1 activation); on the other hand, they protect neurons by triggering anti-inflammatory/neurotrophic M2 activation and by clearing Aβ via phagocytosis. TLRs are associated with Aβ-induced microglial inflammatory activation and Aβ internalization, but the mechanisms remain unclear. In this study, we used real-time surface plasmon resonance spectroscopy and conventional biochemical pull-down assays to demonstrate a direct interaction between TLR2 and the aggregated 42-aa form of human Aβ (Aβ42). TLR2 deficiency reduced Aβ42-triggered inflammatory activation but enhanced Aβ phagocytosis in cultured microglia and macrophages. By expressing TLR2 in HEK293 cells that do not endogenously express TLR2, we observed that TLR2 expression enabled HEK293 cells to respond to Aβ42. Through site-directed mutagenesis of tlr2 gene, we identified the amino acids EKKA (741-744) as a critical cytoplasmic domain for transduction of inflammatory signals. By coexpressing TLR1 or TLR6 in TLR2-transgenic HEK293 cells or silencing tlrs genes in RAW264.7 macrophages, we observed that TLR2-mediated Aβ42-triggered inflammatory activation was enhanced by TLR1 and suppressed by TLR6. Using bone marrow chimeric Alzheimer's amyloid precursor transgenic mice, we observed that TLR2 deficiency in microglia shifts M1- to M2-inflammatory activation in vivo, which was associated with improved neuronal function. Our study demonstrated that TLR2 is a primary receptor for Aβ to trigger neuroinflammatory activation and suggested that inhibition of TLR2 in microglia could be beneficial in Alzheimer's disease pathogenesis.},
  note = {[DOI:\href{http://dx.doi.org/10.4049/jimmunol.1101121}{10.4049/jimmunol.1101121}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/22198949}{22198949}] }
}
@article{pmid21925471,
  author = {Krauthausen, M.  and Ellis, S. L.  and Zimmermann, J.  and Sarris, M.  and Wakefield, D.  and Heneka, M. T.  and Campbell, I. L.  and Muller, M. },
  title = {{O}pposing roles for {C}{X}{C}{R}3 signaling in central nervous system versus ocular inflammation mediated by the astrocyte-targeted production of {I}{L}-12},
  journal = {Am. J. Pathol.},
  year = {2011},
  volume = {179},
  number = {5},
  pages = {2346--2359},
  month = {Nov},
  abstract = {CXCR3 and its ligands are important for the trafficking of activated CD4(+) T(H)1 T cells, CD8(+) T cells, and natural killer cells during inflammation. Recent functional studies demonstrate a more diverse role of CXCR3 in inflammatory diseases of the central nervous system (CNS). We examined the impact of CXCR3 on a less complex interferon-γ-dependent, type 1 cell-mediated immune response in the CNS, induced in mice by the transgenic production of glial fibrillary acidic protein IL-12 (GF-IL12) by astrocytes and retinal Müller cells. GF-IL12 mice develop ataxia because of severe cerebellar inflammation but have little overt ocular disease. Surprisingly, CXCR3-deficient GF-IL12 mice (GF-IL12/CXCR3KO) have drastically reduced ataxia but developed cataracts, severe ocular inflammation, and eye atrophy. Most GF-IL12/CXCR3KO mice had minimal cerebellar inflammation but severe retinal disorganization, loss of photoreceptors, and lens destruction in the eye. The number of CD3(+), CD11b(+), and natural killer 1.1(+) cells were reduced in the CNS but highly increased in the eyes of GF-IL12/CXCR3KO compared with GF-IL12 mice. High levels of interferon-γ, IL-1, tumor necrosis factor α, CXCL9, CXCL10, and CCL5 were found in GF-IL12 cerebelli and GF-IL12/CXCR3KO eyes. Our findings demonstrate key but paradoxical functions for CXCR3 in IL-12-induced immune disease in the CNS, promoting inflammation in the brain yet restricting it in the eye. We conclude that the function of CXCR3 in cellular immune disease is driven by a common trigger and is controlled by tissue-specific factors.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3204010}{PMC3204010}] [DOI:\href{http://dx.doi.org/10.1016/j.ajpath.2011.07.041}{10.1016/j.ajpath.2011.07.041}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/21925471}{21925471}] }
}
@article{pmid21903077,
  author = {Kummer, M. P.  and Hermes, M.  and Delekarte, A.  and Hammerschmidt, T.  and Kumar, S.  and Terwel, D.  and Walter, J.  and Pape, H. C.  and Konig, S.  and Roeber, S.  and Jessen, F.  and Klockgether, T.  and Korte, M.  and Heneka, M. T. },
  title = {{N}itration of tyrosine 10 critically enhances amyloid β aggregation and plaque formation},
  journal = {Neuron},
  year = {2011},
  volume = {71},
  number = {5},
  pages = {833--844},
  month = {Sep},
  abstract = {Part of the inflammatory response in Alzheimer's disease (AD) is the upregulation of the inducible nitric oxide synthase (NOS2) resulting in increased NO production. NO contributes to cell signaling by inducing posttranslational protein modifications. Under pathological conditions there is a shift from the signal transducing actions to the formation of protein tyrosine nitration by secondary products like peroxynitrite and nitrogen dioxide. We identified amyloid β (Aβ) as an NO target, which is nitrated at tyrosine 10 (3NTyr(10)-Aβ). Nitration of Aβ accelerated its aggregation and was detected in the core of Aβ plaques of APP/PS1 mice and AD brains. NOS2 deficiency or oral treatment with the NOS2 inhibitor L-NIL strongly decreased 3NTyr(10)-Aβ, overall Aβ deposition and cognitive dysfunction in APP/PS1 mice. Further, injection of 3NTyr(10)-Aβ into the brain of young APP/PS1 mice induced β-amyloidosis. This suggests a disease modifying role for NOS2 in AD and therefore represents a potential therapeutic target.},
  note = {[DOI:\href{http://dx.doi.org/10.1016/j.neuron.2011.07.001}{10.1016/j.neuron.2011.07.001}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/21903077}{21903077}] }
}
@article{pmid21813677,
  author = {Mildner, A.  and Schlevogt, B.  and Kierdorf, K.  and Bottcher, C.  and Erny, D.  and Kummer, M. P.  and Quinn, M.  and Bruck, W.  and Bechmann, I.  and Heneka, M. T.  and Priller, J.  and Prinz, M. },
  title = {{D}istinct and non-redundant roles of microglia and myeloid subsets in mouse models of {A}lzheimer's disease},
  journal = {J. Neurosci.},
  year = {2011},
  volume = {31},
  number = {31},
  pages = {11159--11171},
  month = {Aug},
  abstract = {Mononuclear phagocytes are important modulators of Alzheimer's disease (AD), but the specific functions of resident microglia, bone marrow-derived mononuclear cells, and perivascular macrophages have not been resolved. To elucidate the spatiotemporal roles of mononuclear phagocytes during disease, we targeted myeloid cell subsets from different compartments and examined disease pathogenesis in three different mouse models of AD (APP(swe/PS1), APP(swe), and APP23 mice). We identified chemokine receptor 2 (CCR2)-expressing myeloid cells as the population that was preferentially recruited to β-amyloid (Aβ) deposits. Unexpectedly, AD brains with dysfunctional microglia and devoid of parenchymal bone marrow-derived phagocytes did not show overt changes in plaque pathology and Aβ load. In contrast, restriction of CCR2 deficiency to perivascular myeloid cells drastically impaired β-amyloid clearance and amplified vascular Aβ deposition, while parenchymal plaque deposition remained unaffected. Together, our data advocate selective functions of CCR2-expressing myeloid subsets, which could be targeted specifically to modify disease burden in AD.},
  note = {[DOI:\href{http://dx.doi.org/10.1523/JNEUROSCI.6209-10.2011}{10.1523/JNEUROSCI.6209-10.2011}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/21813677}{21813677}] }
}
@article{pmid21784349,
  author = {Mattsson, N.  and Andreasson, U.  and Persson, S.  and Arai, H.  and Batish, S. D.  and Bernardini, S.  and Bocchio-Chiavetto, L.  and Blankenstein, M. A.  and Carrillo, M. C.  and Chalbot, S.  and Coart, E.  and Chiasserini, D.  and Cutler, N.  and Dahlfors, G.  and Duller, S.  and Fagan, A. M.  and Forlenza, O.  and Frisoni, G. B.  and Galasko, D.  and Galimberti, D.  and Hampel, H.  and Handberg, A.  and Heneka, M. T.  and Herskovits, A. Z.  and Herukka, S. K.  and Holtzman, D. M.  and Humpel, C.  and Hyman, B. T.  and Iqbal, K.  and Jucker, M.  and Kaeser, S. A.  and Kaiser, E.  and Kapaki, E.  and Kidd, D.  and Klivenyi, P.  and Knudsen, C. S.  and Kummer, M. P.  and Lui, J.  and Llado, A.  and Lewczuk, P.  and Li, Q. X.  and Martins, R.  and Masters, C.  and McAuliffe, J.  and Mercken, M.  and Moghekar, A.  and Molinuevo, J. L.  and Montine, T. J.  and Nowatzke, W.  and O'Brien, R.  and Otto, M.  and Paraskevas, G. P.  and Parnetti, L.  and Petersen, R. C.  and Prvulovic, D.  and de Reus, H. P.  and Rissman, R. A.  and Scarpini, E.  and Stefani, A.  and Soininen, H.  and Schroder, J.  and Shaw, L. M.  and Skinningsrud, A.  and Skrogstad, B.  and Spreer, A.  and Talib, L.  and Teunissen, C.  and Trojanowski, J. Q.  and Tumani, H.  and Umek, R. M.  and Van Broeck, B.  and Vanderstichele, H.  and Vecsei, L.  and Verbeek, M. M.  and Windisch, M.  and Zhang, J.  and Zetterberg, H.  and Blennow, K. },
  title = {{T}he {A}lzheimer's {A}ssociation external quality control program for cerebrospinal fluid biomarkers},
  journal = {Alzheimers Dement},
  year = {2011},
  volume = {7},
  number = {4},
  pages = {386--395},
  month = {Jul},
  abstract = {The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)-42, total-tau (T-tau), and phosphorylated-tau (P-tau) demonstrate good diagnostic accuracy for Alzheimer's disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer's Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch-to-batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program.\\ The program is open for laboratories using commercially available kits for Aβ, T-tau, or P-tau. CSF samples (aliquots of pooled CSF) are sent for analysis several times a year from the Clinical Neurochemistry Laboratory at the Mölndal campus of the University of Gothenburg, Sweden. Each round consists of three quality control samples.\\ Forty laboratories participated. Twenty-six used INNOTEST enzyme-linked immunosorbent assay kits, 14 used Luminex xMAP with the INNO-BIA AlzBio3 kit (both measure Aβ-(1-42), P-tau(181P), and T-tau), and 5 used Meso Scale Discovery with the Aβ triplex (AβN-42, AβN-40, and AβN-38) or T-tau kits. The total coefficients of variation between the laboratories were 13\% to 36\%. Five laboratories analyzed the samples six times on different occasions. Within-laboratory precisions differed considerably between biomarkers within individual laboratories.\\ Measurements of CSF AD biomarkers show large between-laboratory variability, likely caused by factors related to analytical procedures and the analytical kits. Standardization of laboratory procedures and efforts by kit vendors to increase kit performance might lower variability, and will likely increase the usefulness of CSF AD biomarkers.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710290}{PMC3710290}] [DOI:\href{http://dx.doi.org/10.1016/j.jalz.2011.05.2243}{10.1016/j.jalz.2011.05.2243}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/21784349}{21784349}] }
}
@article{pmid21752601,
  author = {Juckel, G.  and Manitz, M. P.  and Brune, M.  and Friebe, A.  and Heneka, M. T.  and Wolf, R. J. },
  title = {{M}icroglial activation in a neuroinflammational animal model of schizophrenia--a pilot study},
  journal = {Schizophr. Res.},
  year = {2011},
  volume = {131},
  number = {1-3},
  pages = {96--100},
  month = {Sep},
  abstract = {Inflammatory and immunological processes interfering with brain development are discussed as one cause of schizophrenia. Various signs of overactivation of the immune system were often found in this disease. Based on post-mortem analysis showing an increased number of activated microglial cells in patients with schizophrenia, it can be hypothesized that these cells contribute to disease pathogenesis and may actively be involved in gray matter loss observed in such patients. In the present study, PolyI:C incubation of pregnant dams was used as animal model of schizophrenia, and the number and shape of microglia were assessed in the offspring in the early phase of this disease, using fluorescence immunostaining (Iba1). Descendants of mice exposed to PolyI:C at embryonic day 9 showed higher number of microglial cells in the hippocampus and striatum, but not in the frontal cortex at postnatal day 30, which is similarly to adolescence in man, as compared to those exposed to saline. Furthermore, offspring microglia from PolyI:C treated mothers were morphologically characterized by a reduced arborization indicative for a status of higher activation compared to the offspring microglia from vehicle treated mice. This study supports the hypothesis that maternal infection during embryogenesis contributes to microglial activation in the offspring, which may therefore represent a contributing factor to the pathogenesis of schizophrenia and underlines the need for new pharmacological treatment options in this regard.},
  note = {[DOI:\href{http://dx.doi.org/10.1016/j.schres.2011.06.018}{10.1016/j.schres.2011.06.018}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/21752601}{21752601}] }
}
@article{pmid21562267,
  author = {Terwel, D.  and Steffensen, K. R.  and Verghese, P. B.  and Kummer, M. P.  and Gustafsson, J. A.  and Holtzman, D. M.  and Heneka, M. T. },
  title = {{C}ritical role of astroglial apolipoprotein {E} and liver {X} receptor-α expression for microglial {A}β phagocytosis},
  journal = {J. Neurosci.},
  year = {2011},
  volume = {31},
  number = {19},
  pages = {7049--7059},
  month = {May},
  abstract = {Liver X receptors (LXRs) regulate immune cell function and cholesterol metabolism, both factors that are critically involved in Alzheimer's disease (AD). To investigate the therapeutic potential of long-term LXR activation in amyloid-β (Aβ) peptide deposition in an AD model, 13-month-old, amyloid plaque-bearing APP23 mice were treated with the LXR agonist TO901317. Postmortem analysis demonstrated that TO901317 efficiently crossed the blood-brain barrier. Insoluble and soluble Aβ levels in the treated APP23 mice were reduced by 80\% and 40\%, respectively, compared with untreated animals. Amyloid precursor protein (APP) processing, however, was hardly changed by the compound, suggesting that the observed effects were instead mediated by Aβ disposal. Despite the profound effect on Aβ levels, spatial learning in the Morris water maze was only slightly improved by the treatment. ABCA1 (ATP-binding cassette transporter 1) and apolipoprotein E (ApoE) protein levels were increased and found to be primarily localized in astrocytes. Experiments using primary microglia demonstrated that medium derived from primary astrocytes exposed to TO901317 stimulated phagocytosis of fibrillar Aβ. Conditioned medium from TO901317-treated ApoE(-/-) or LXRα(-/-) astrocytes did not increase phagocytosis of Aβ. In APP23 mice, long-term treatment with TO901317 strongly increased the association of microglia and Aβ plaques. Short-term treatment of APP/PS1 mice with TO901317 also increased this association, which was dependent on the presence of LXRα and was accompanied by increased ApoE lipidation. Together, these data suggest that astrocytic LXRα activation and subsequent release of ApoE by astrocytes is critical for the ability of microglia to remove fibrillar Aβ in response to treatment with TO901317.},
  note = {[DOI:\href{http://dx.doi.org/10.1523/JNEUROSCI.6546-10.2011}{10.1523/JNEUROSCI.6546-10.2011}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/21562267}{21562267}] }
}
@article{pmid21527912,
  author = {Kumar, S.  and Rezaei-Ghaleh, N.  and Terwel, D.  and Thal, D. R.  and Richard, M.  and Hoch, M.  and Mc Donald, J. M.  and Wullner, U.  and Glebov, K.  and Heneka, M. T.  and Walsh, D. M.  and Zweckstetter, M.  and Walter, J. },
  title = {{E}xtracellular phosphorylation of the amyloid β-peptide promotes formation of toxic aggregates during the pathogenesis of {A}lzheimer's disease},
  journal = {EMBO J.},
  year = {2011},
  volume = {30},
  number = {11},
  pages = {2255--2265},
  month = {Jun},
  abstract = {Alzheimer's disease (AD) is the most common form of dementia and associated with progressive deposition of amyloid β-peptides (Aβ) in the brain. Aβ derives by sequential proteolytic processing of the amyloid precursor protein by β- and γ-secretases. Rare mutations that lead to amino-acid substitutions within or close to the Aβ domain promote the formation of neurotoxic Aβ assemblies and can cause early-onset AD. However, mechanisms that increase the aggregation of wild-type Aβ and cause the much more common sporadic forms of AD are largely unknown. Here, we show that extracellular Aβ undergoes phosphorylation by protein kinases at the cell surface and in cerebrospinal fluid of the human brain. Phosphorylation of serine residue 8 promotes formation of oligomeric Aβ assemblies that represent nuclei for fibrillization. Phosphorylated Aβ was detected in the brains of transgenic mice and human AD brains and showed increased toxicity in Drosophila models as compared with non-phosphorylated Aβ. Phosphorylation of Aβ could represent an important molecular mechanism in the pathogenesis of the most common sporadic form of AD.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3117653}{PMC3117653}] [DOI:\href{http://dx.doi.org/10.1038/emboj.2011.138}{10.1038/emboj.2011.138}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/21527912}{21527912}] }
}
@article{pmid21517843,
  author = {Terwel, D.  and Loschmann, Y. N.  and Schmidt, H. H.  and Scholer, H. R.  and Cantz, T.  and Heneka, M. T. },
  title = {{N}euroinflammatory and behavioural changes in the {A}tp7{B} mutant mouse model of {W}ilson's disease},
  journal = {J. Neurochem.},
  year = {2011},
  volume = {118},
  number = {1},
  pages = {105--112},
  month = {Jul},
  abstract = {Wilson's disease (WD) is caused by mutations in the copper transporting ATPase 7B (Atp7b). Patients present with liver pathology or behavioural disturbances. Studies on rodent models for WD so far mainly focussed on liver, not brain. The effect of knockout of atp7b on sensori-motor and cognitive behaviour, as well as neuronal number, inflammatory markers, copper and synaptic proteins in brain were studied in so-called toxic milk mice. Copper accumulated in striatum and hippocampus of toxic milk mice, but not in cerebral cortex. Inflammatory markers were increased in striatum and corpus callosum, but not in cerebral cortex and hippocampus, whereas neuronal numbers were unchanged. Toxic milk mice were mildly impaired in the rotarod and cylinder test and unable to acquire spatial memory in the Morris water maze. Despite the latter observation only synaptophysin of a number of synaptic proteins, was altered in the hippocampus of toxic milk mice. In addition to disturbances in neuronal signalling by increased brain copper, inflammation and inflammatory signalling from the periphery to the brain might add to the behavioural disturbances in the toxic milk mice. These mice can be used to evaluate therapeutic strategies to alleviate behavioural disturbances and cerebral pathology observed in WD.},
  note = {[DOI:\href{http://dx.doi.org/10.1111/j.1471-4159.2011.07278.x}{10.1111/j.1471-4159.2011.07278.x}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/21517843}{21517843}] }
}
@article{pmid21345168,
  author = {Heneka, M. T.  and Kummer, M. P.  and Weggen, S.  and Bulic, B.  and Multhaup, G.  and Munter, L.  and Hull, M.  and Pflanzner, T.  and Pietrzik, C. U. },
  title = {{M}olecular mechanisms and therapeutic application of {N}{S}{A}{I}{D}s and derived compounds in {A}lzheimer's disease},
  journal = {Curr Alzheimer Res},
  year = {2011},
  volume = {8},
  number = {2},
  pages = {115--131},
  month = {Mar},
  abstract = {Alzheimer's disease (AD) is the most common form of neurodegenerative dementias worldwide. Amyloid-β deposition, neurofibrillary tangle formation and Neuroinflammation are the major pathogenetic mechanisms that in concert lead to memory dysfunction and decline of cognition. To date, there is no curative treatment for AD. Epidemiological analysis support the notion that sustained intake of non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk and delay the onset of AD. In contrast, therapeutic studies testing NSAID efficacy in AD patients have not yielded positive results. This suggests that either the investigated drugs have not addressed the mechanism of action required for mediating beneficial effects or that NSAIDs are effective at stages way before clinical onset of symptoms. The NSAIDs concerned are pleiotrophic in nature and interact with more than one pathomechanism. Therefore evidence for more than one neuroprotective action of NSAIDs has been put forward and it seems likely that some of the drugs act at multiple levels through more than one molecular mechanism. Some, even may not only be beneficial, but negative actions may be overruled by protective effects. Within these mechanisms, modulation of γ-secretase activity, the activation of the peroxisome proliferator-activated receptor-γ, binding to prostaglandin receptors or interactions at the blood-brain barrier may account for the observed protection from AD. This article reviews the current knowledge and views on the above mechanisms and critically discusses current obstacles and the potential as future AD therapeutics.},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/21345168}{21345168}] }
}
@article{pmid21129451,
  author = {Jardanhazi-Kurutz, D.  and Kummer, M. P.  and Terwel, D.  and Vogel, K.  and Thiele, A.  and Heneka, M. T. },
  title = {{D}istinct adrenergic system changes and neuroinflammation in response to induced locus ceruleus degeneration in {A}{P}{P}/{P}{S}1 transgenic mice},
  journal = {Neuroscience},
  year = {2011},
  volume = {176},
  pages = {396--407},
  month = {Mar},
  abstract = {Degeneration of locus ceruleus (LC) neurons and subsequent reduction of norepinephrine (NE) in LC projection areas represent an early pathological indicator of Alzheimer's disease (AD). In order to study the effects of NE depletion on cortical and hippocampal adrenergic system changes, LC degeneration was induced in 3-month-old APP/PS1 mice by the neurotoxin N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (dsp4). Dsp4 induced a widespread loss of norepinephrine transporter binding in multiple brain structures already at 4.5 months. This was accompanied by changes of α-1-, α-2-, and β-1-adreneroceptor binding sites as well as altered adrenoceptor mRNA expression. In parallel, we observed increased micro- and astrogliosis in cortical and hippocampal structures in dsp4-treated groups. In addition, the expression of the pro-inflammatory cytokines CCL2 and IL-1β were induced in both, dsp4-treated and APP/PS1-transgenic mice, whereas IL-1α was only up-regulated in dsp4-treated APP/PS1 mice. Concerning amyloid β (Aβ) deposition, we observed an elevation of Aβ1-42 levels in aged dsp4-treated APP/PS1 mice. These data support the hypothesis that LC degeneration leads to dysregulation of adrenergic receptors and exacerbation of Aβ-induced neuroinflammation, both of which are exploitable for early disease marker development.},
  note = {[DOI:\href{http://dx.doi.org/10.1016/j.neuroscience.2010.11.052}{10.1016/j.neuroscience.2010.11.052}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/21129451}{21129451}] }
}
@article{pmid21109328,
  author = {Rey, N. L.  and Jardanhazi-Kurutz, D.  and Terwel, D.  and Kummer, M. P.  and Jourdan, F.  and Didier, A.  and Heneka, M. T. },
  title = {{L}ocus coeruleus degeneration exacerbates olfactory deficits in {A}{P}{P}/{P}{S}1 transgenic mice},
  journal = {Neurobiol. Aging},
  year = {2012},
  volume = {33},
  number = {2},
  pages = {1--11},
  month = {Feb},
  abstract = {Neuronal loss in the locus coeruleus (LC) is 1 of the early pathological events in Alzheimer's disease (AD). Projections of noradrenergic neurons of the LC innervate the olfactory bulb (OB). Because olfactory deficits have been reported in early AD, we investigated the effect of induced LC degeneration on olfactory memory and discrimination in an AD mouse model. LC degeneration was induced by treating APP/PS1 mice with N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (DSP4) repeatedly between 3 and 12 months of age. Short term odor retention, ability for spontaneous habituation to an odor, and spontaneous odor discrimination were assessed by behavioral tests. DSP4 treatment in APP/PS1 mice resulted in an exacerbation of short term olfactory memory deficits and more discrete weakening of olfactory discrimination abilities, suggesting that LC degeneration contributes to olfactory deficits observed in AD. Importantly, DSP4 treatment also increased amyloid β (Aβ) deposition in the olfactory bulb of APP/PS1 mice, which correlated with olfactory memory, not with discrimination deficits.},
  note = {[DOI:\href{http://dx.doi.org/10.1016/j.neurobiolaging.2010.10.009}{10.1016/j.neurobiolaging.2010.10.009}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/21109328}{21109328}] }
}
@article{pmid21044080,
  author = {Perez Nievas, B. G.  and Hammerschmidt, T.  and Kummer, M. P.  and Terwel, D.  and Leza, J. C.  and Heneka, M. T. },
  title = {{R}estraint stress increases neuroinflammation independently of amyloid β levels in amyloid precursor protein/{P}{S}1 transgenic mice},
  journal = {J. Neurochem.},
  year = {2011},
  volume = {116},
  number = {1},
  pages = {43--52},
  month = {Jan},
  abstract = {Both hypercortisolemia and hippocampal damage are features found in patients diagnosed of Alzheimer's disease (AD) and epidemiological evidence supports a role for stress as a risk factor for AD. It is known that immobilization stress is followed by accumulation of oxidative/nitrosative mediators in brain after the release of proinflammatory cytokines, nuclear factor kappa B activation, nitric oxide synthase-2 and cyclooxygenase-2 expression. Long-term exposure to elevated corticosteroid levels is known to affect the hippocampus which plays a central role in the regulation of the hypothalamic-pituitary-adrenal axis. We therefore studied the effect of chronic immobilization stress on amyloid precursor protein/PS1 mice. Stress exposure increased AD-induced neuroinflammation characterized by astrogliosis, increased inflammatory gene transcription and lipid peroxidation. Importantly, immobilization stress did not increase the soluble or insoluble amyloid β levels suggesting that increased cortisol levels lower the threshold for a neuroinflammatory response, independently from amyloid β. Since inflammation may act as a factor that contributes disease progression, the stress-inflammation relation described here may be relevant to understand the initial mechanisms in underlying the risk enhancing action of stress on AD.},
  note = {[DOI:\href{http://dx.doi.org/10.1111/j.1471-4159.2010.07083.x}{10.1111/j.1471-4159.2010.07083.x}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/21044080}{21044080}] }
}
@article{pmid20937084,
  author = {Fleisher-Berkovich, S.  and Filipovich-Rimon, T.  and Ben-Shmuel, S.  and Hulsmann, C.  and Kummer, M. P.  and Heneka, M. T. },
  title = {{D}istinct modulation of microglial amyloid β phagocytosis and migration by neuropeptides (i)},
  journal = {J Neuroinflammation},
  year = {2010},
  volume = {7},
  pages = {61},
  abstract = {Microglial activation plays an integral role in the development and course of neurodegeneration. Although neuropeptides such as bradykinin (BK), somatostatin (SST), and endothelin (ET) are known to be important mediators of inflammation in the periphery, evidence of a similar function in brain is scarce. Using immunocytochemistry, we demonstrate the expression of receptors for BK (B1, B2 subtypes), ET (ETA, ETB subtypes) and SST (SST 2, 3, 4 subtypes) in primary microglia and microglial cell lines. Exposure of BV2 and N9, as well as primary microglial cells to BK or SST increased Aβ uptake in a concentration-dependent manner, whereas endothelin decreased Aβ uptake. This was caused by increased phagocytosis of Aβ since the rate of intracellular Aβ degradation remained unaffected. All neuropeptides increased chemotactic activity of microglia. In addition, BK reduced Aβ-induced expression of proinflammatory genes including iNOS and COX-2. ET decreased the Aβ-induced expression of monocyte chemoattractant protein 1 and interleukin-6. These results suggest that neuropeptides play an important role in chemotaxis and Aβ clearance and modulate the brain's response to neuroinflammatory processes.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964654}{PMC2964654}] [DOI:\href{http://dx.doi.org/10.1186/1742-2094-7-61}{10.1186/1742-2094-7-61}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/20937084}{20937084}] }
}
@article{pmid20876579,
  author = {Tamboli, I. Y.  and Barth, E.  and Christian, L.  and Siepmann, M.  and Kumar, S.  and Singh, S.  and Tolksdorf, K.  and Heneka, M. T.  and Lutjohann, D.  and Wunderlich, P.  and Walter, J. },
  title = {{S}tatins promote the degradation of extracellular amyloid {beta}-peptide by microglia via stimulation of exosome-associated insulin-degrading enzyme ({I}{D}{E}) secretion},
  journal = {J. Biol. Chem.},
  year = {2010},
  volume = {285},
  number = {48},
  pages = {37405--37414},
  month = {Nov},
  abstract = {Epidemiological studies indicate that intake of statins decrease the risk of developing Alzheimer disease. Cellular and in vivo studies suggested that statins might decrease the generation of the amyloid β-peptide (Aβ) from the β-amyloid precursor protein. Here, we show that statins potently stimulate the degradation of extracellular Aβ by microglia. The statin-dependent clearance of extracellular Aβ is mainly exerted by insulin-degrading enzyme (IDE) that is secreted in a nonconventional pathway in association with exosomes. Stimulated IDE secretion and Aβ degradation were also observed in blood of mice upon peripheral treatment with lovastatin. Importantly, increased IDE secretion upon lovastatin treatment was dependent on protein isoprenylation and up-regulation of exosome secretion by fusion of multivesicular bodies with the plasma membrane. These data demonstrate a novel pathway for the nonconventional secretion of IDE via exosomes. The modulation of this pathway could provide a new strategy to enhance the extracellular clearance of Aβ.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2988346}{PMC2988346}] [DOI:\href{http://dx.doi.org/10.1074/jbc.M110.149468}{10.1074/jbc.M110.149468}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/20876579}{20876579}] }
}
@article{pmid20632195,
  author = {Heneka, M. T.  and O'Banion, M. K.  and Terwel, D.  and Kummer, M. P. },
  title = {{N}euroinflammatory processes in {A}lzheimer's disease},
  journal = {J Neural Transm},
  year = {2010},
  volume = {117},
  number = {8},
  pages = {919--947},
  month = {Aug},
  abstract = {Generation of neurotoxic amyloid beta peptides and their deposition along with neurofibrillary tangle formation represent key pathological hallmarks in Alzheimer's disease (AD). Recent evidence suggests that inflammation may be a third important component which, once initiated in response to neurodegeneration or dysfunction, may actively contribute to disease progression and chronicity. Various neuroinflammatory mediators including complement activators and inhibitors, chemokines, cytokines, radical oxygen species and inflammatory enzyme systems are expressed and released by microglia, astrocytes and neurons in the AD brain. Degeneration of aminergic brain stem nuclei including the locus ceruleus and the nucleus basalis of Meynert may facilitate the occurrence of inflammation in their projection areas given the antiinflammatory and neuroprotective action of their key transmitters norepinephrine and acetylcholine. While inflammation has been thought to arise secondary to degeneration, recent experiments demonstrated that inflammatory mediators may stimulate amyloid precursor protein processing by various means and therefore can establish a vicious cycle. Despite the fact that some aspects of inflammation may even be protective for bystander neurons, antiinflammatory treatment strategies should therefore be considered. Non-steroidal anti-inflammatory drugs have been shown to reduce the risk and delay the onset to develop AD. While, the precise molecular mechanism underlying this effect is still unknown, a number of possible mechanisms including cyclooxygenase 2 or gamma-secretase inhibition and activation of the peroxisome proliferator activated receptor gamma may alone or, more likely, in concert account for the epidemiologically observed protection.},
  note = {[DOI:\href{http://dx.doi.org/10.1007/s00702-010-0438-z}{10.1007/s00702-010-0438-z}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/20632195}{20632195}] }
}
@article{pmid20567962,
  author = {Heneka, M. T. },
  title = {[{C}ourse modifying therapy of {A}lzheimer's dementia]},
  journal = {Nervenarzt},
  year = {2010},
  volume = {81},
  number = {7},
  pages = {807--808},
  month = {Jul},
  abstract = {The current therapy of Alzheimer's disease is primarily symptomatic. Drugs which aim to modify the course of the disease are currently being developed and tested in clinical trials. Given the complex and partly unknown pathogenesis of the disease, failure of such forms of therapy has to be taken into account. Clinical epidemiology suggests a possible neuroprotective effect of statins and non-steroidal anti-inflammatory drugs, however, the molecular basis of these effects has to be further unraveled. Therapies that modify the course of Alzheimer's disease are only likely to be effective years if not decades before the disease becomes clinically apparent. Thus, the therapy of risk factors including arterial hypertension and obesity in midlife as well as a Mediterranean diet currently provides the highest chance of modifying the course of the disease.},
  note = {[DOI:\href{http://dx.doi.org/10.1007/s00115-010-3000-1}{10.1007/s00115-010-3000-1}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/20567962}{20567962}] }
}
@article{pmid20231476,
  author = {Heneka, M. T.  and Nadrigny, F.  and Regen, T.  and Martinez-Hernandez, A.  and Dumitrescu-Ozimek, L.  and Terwel, D.  and Jardanhazi-Kurutz, D.  and Walter, J.  and Kirchhoff, F.  and Hanisch, U. K.  and Kummer, M. P. },
  title = {{L}ocus ceruleus controls {A}lzheimer's disease pathology by modulating microglial functions through norepinephrine},
  journal = {Proc. Natl. Acad. Sci. U.S.A.},
  year = {2010},
  volume = {107},
  number = {13},
  pages = {6058--6063},
  month = {Mar},
  abstract = {Locus ceruleus (LC)-supplied norepinephrine (NE) suppresses neuroinflammation in the brain. To elucidate the effect of LC degeneration and subsequent NE deficiency on Alzheimer's disease pathology, we evaluated NE effects on microglial key functions. NE stimulation of mouse microglia suppressed Abeta-induced cytokine and chemokine production and increased microglial migration and phagocytosis of Abeta. Induced degeneration of the locus ceruleus increased expression of inflammatory mediators in APP-transgenic mice and resulted in elevated Abeta deposition. In vivo laser microscopy confirmed a reduced recruitment of microglia to Abeta plaque sites and impaired microglial Abeta phagocytosis in NE-depleted APP-transgenic mice. Supplying the mice the norepinephrine precursor L-threo-DOPS restored microglial functions in NE-depleted mice. This indicates that decrease of NE in locus ceruleus projection areas facilitates the inflammatory reaction of microglial cells in AD and impairs microglial migration and phagocytosis, thereby contributing to reduced Abeta clearance. Consequently, therapies targeting microglial phagocytosis should be tested under NE depletion.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2851853}{PMC2851853}] [DOI:\href{http://dx.doi.org/10.1073/pnas.0909586107}{10.1073/pnas.0909586107}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/20231476}{20231476}] }
}
@article{pmid20144675,
  author = {Jardanhazi-Kurutz, D.  and Kummer, M. P.  and Terwel, D.  and Vogel, K.  and Dyrks, T.  and Thiele, A.  and Heneka, M. T. },
  title = {{I}nduced {L}{C} degeneration in {A}{P}{P}/{P}{S}1 transgenic mice accelerates early cerebral amyloidosis and cognitive deficits},
  journal = {Neurochem. Int.},
  year = {2010},
  volume = {57},
  number = {4},
  pages = {375--382},
  month = {Nov},
  abstract = {Degeneration of locus ceruleus neurons and subsequent reduction of norepinephrine concentration in locus ceruleus projection areas represent an early pathological indicator of Alzheimer's disease. In order to model the pathology of the human disease and to study the effects of norepinephrine-depletion on amyloid precursor protein processing, behaviour, and neuroinflammation, locus ceruleus degeneration was induced in mice coexpressing the swedish mutant of the amyloid precursor protein and the presenilin 1 DeltaExon 9 mutant (APP/PS1) using the neurotoxin N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (dsp4) starting treatment at 3 months of age. Norepinephrine transporter immunolabelling demonstrated severe loss of locus ceruleus neurons and loss of cortical norepinephrine transporter starting as early as 4.5 months of age and aggravating over time. Of note, dsp4-treated transgenic mice showed elevated amyloid beta levels and impaired spatial memory performance at 6.5 months of age compared to control-treated APP/PS1 transgenic mice, indicating an accelerating effect on cerebral amyloidosis and cognitive deficits. Likewise, norepinephrine-depletion increased neuroinflammation compared to transgenic controls as verified by macrophage inflammatory protein-1alpha and -1beta gene expression analysis. Exploratory activity and memory retention was compromised by age in APP/PS1 transgenic mice and further aggravated by induced noradrenergic deficiency. In contrast, novel object recognition was not influenced by norepinephrine deficiency, but by the APP/PS1 transgene at 12 months. Overall, our data indicate that early loss of noradrenergic innervation promotes amyloid deposition and modulates the activation state of inflammatory cells. This in turn could have had impact on the acceleration of cognitive deficits observed over time.},
  note = {[DOI:\href{http://dx.doi.org/10.1016/j.neuint.2010.02.001}{10.1016/j.neuint.2010.02.001}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/20144675}{20144675}] }
}
@article{pmid20064241,
  author = {Schlachetzki, J. C.  and Fiebich, B. L.  and Haake, E.  and de Oliveira, A. C.  and Candelario-Jalil, E.  and Heneka, M. T.  and Hull, M. },
  title = {{N}orepinephrine enhances the {L}{P}{S}-induced expression of {C}{O}{X}-2 and secretion of {P}{G}{E}2 in primary rat microglia},
  journal = {J Neuroinflammation},
  year = {2010},
  volume = {7},
  pages = {2},
  abstract = {Recent studies suggest an important role for neurotransmitters as modulators of inflammation. Neuroinflammatory mediators such as cytokines and molecules of the arachidonic acid pathway are generated and released by microglia. The monoamine norepinephrine reduces the production of cytokines by activated microglia in vitro. However, little is known about the effects of norepinephrine on prostanoid synthesis. In the present study, we investigate the role of norepinephrine on cyclooxygenase- (COX-)2 expression/synthesis and prostaglandin (PG)E2 production in rat primary microglia.\\ Interestingly, norepinephrine increased COX-2 mRNA, but not protein expression. Norepinephrine strongly enhanced COX-2 expression and PGE2 production induced by lipopolysaccharide (LPS). This effect is likely to be mediated by beta-adrenoreceptors, since beta-, but not alpha-adrenoreceptor agonists produced similar results. Furthermore, beta-adrenoreceptor antagonists blocked the enhancement of COX-2 levels induced by norepinephrine and beta-adrenoreceptor agonists.\\ Considering that PGE2 displays different roles in neuroinflammatory and neurodegenerative disorders, norepinephrine may play an important function in the modulation of these processes in pathophysiological conditions.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2819253}{PMC2819253}] [DOI:\href{http://dx.doi.org/10.1186/1742-2094-7-2}{10.1186/1742-2094-7-2}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/20064241}{20064241}] }
}
@article{pmid19944719,
  author = {Heneka, M. T.  and Rodriguez, J. J.  and Verkhratsky, A. },
  title = {{N}euroglia in neurodegeneration},
  journal = {Brain Res Rev},
  year = {2010},
  volume = {63},
  number = {1-2},
  pages = {189--211},
  month = {May},
  abstract = {Neuroglial cells are fundamental for control of brain homeostasis and they represent the intrinsic brain defence system. All forms in neuropathology therefore inevitably involve glia. The neurodegenerative diseases disrupt connectivity within brain circuits affecting neuronal-neuronal, neuronal-glial and glial-glial contacts. In addition neurodegenerative processes trigger universal and conserved glial reactions represented by astrogliosis and microglial activation. The complex of recently acquired knowledge allows us to regard the neurodegenerative diseases as primarily gliodegenerative processes, in which glial cells determine the progression and outcome of neuropathological process.},
  note = {[DOI:\href{http://dx.doi.org/10.1016/j.brainresrev.2009.11.004}{10.1016/j.brainresrev.2009.11.004}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/19944719}{19944719}] }
}
@article{pmid19906966,
  author = {Weberpals, M.  and Hermes, M.  and Hermann, S.  and Kummer, M. P.  and Terwel, D.  and Semmler, A.  and Berger, M.  and Schafers, M.  and Heneka, M. T. },
  title = {{N}{O}{S}2 gene deficiency protects from sepsis-induced long-term cognitive deficits},
  journal = {J. Neurosci.},
  year = {2009},
  volume = {29},
  number = {45},
  pages = {14177--14184},
  month = {Nov},
  abstract = {To date, long-term consequences of septic encephalopathy on cerebral metabolism, cognition, learning, and memory capabilities and factors involved are poorly understood. In this study, we used a murine sepsis model to demonstrate that bacterial lipopolysaccharide (LPS) causes long-term cognitive deficits in mice. Two months after LPS treatment, wild-type mice committed more working and reference memory errors than controls. The behavioral impairment was independent of the cerebral glucose uptake as evidenced by (18)F-Fluordeoxyglucose small animal positron emission tomography. In contrast, mice deficient for the inducible nitric oxide synthase gene (NOS2-/-) did not show any cognitive changes when challenged with LPS. Immunohistochemical analysis demonstrated that LPS did not lead to neuronal cell death but caused sustained microglial activation in wild-type as compared to NOS2-/- mice. Expression analysis showed that LPS-treated NOS2-/- mice had lower brain mRNA levels for proinflammatory factors compared with wild-type mice. Expression analysis demonstrated distinct changes in the content of synaptic proteins in wild-type mice, which were not observed in the NOS2-/- mice. Together, this data set outlines the importance of the NOS2 activation for long-term cerebral changes after severe sepsis.},
  note = {[DOI:\href{http://dx.doi.org/10.1523/JNEUROSCI.3238-09.2009}{10.1523/JNEUROSCI.3238-09.2009}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/19906966}{19906966}] }
}
@article{pmid19457135,
  author = {Papi, A.  and Tatenhorst, L.  and Terwel, D.  and Hermes, M.  and Kummer, M. P.  and Orlandi, M.  and Heneka, M. T. },
  title = {{P}{P}{A}{R}gamma and {R}{X}{R}gamma ligands act synergistically as potent antineoplastic agents in vitro and in vivo glioma models},
  journal = {J. Neurochem.},
  year = {2009},
  volume = {109},
  number = {6},
  pages = {1779--1790},
  month = {Jun},
  abstract = {Glioblastoma represent the most common primary brain tumor in adults and are currently considered incurable. We investigated antiproliferative and anti-invasive mechanisms of 6-OH-11-O-hydroxyfenantrene (IIF), a retinoid X receptor ligand, and pioglitazone (PGZ), a peroxisome proliferator-activated receptor gamma activator, in three different glioblastoma cell lines. A dose-dependent reduction of tumor invasion and strong decrease of matrix metalloproteinases 2 and 9 expression was observed, especially when a combination therapy of IIF and PGZ was administered. Combined treatment also markedly reduced proliferation and induced apoptosis in all glioma cell lines tested. This was in particular accompanied by decrease of antiapoptotic proteins Bcl2 and p53, while simultaneously pro-apoptotic cytochrome c, cleaved caspase 3, Bax and Bad levels increased. These in vitro findings were further substantiated in a murine glioma model in vivo, where oral administration of PGZ and IIF resulted in significantly reduced tumor volume and proliferation. Of note, treatment with nuclear receptor ligands was not only effective when the treatment was initiated shortly after the intraparenchymal seeding of the glioma cells, but even when initiated in the last third of the observation period. Collectively, our results demonstrate the effectiveness of a combined treatment of ligands of proliferator-activated receptor and retinoid X receptor against glioblastoma.},
  note = {[DOI:\href{http://dx.doi.org/10.1111/j.1471-4159.2009.06111.x}{10.1111/j.1471-4159.2009.06111.x}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/19457135}{19457135}] }
}
@article{pmid19328200,
  author = {Heneka, M. T. },
  title = {{N}oradrenergic denervation facilitates the release of acetylcholine and serotonin in the hippocampus: towards a mechanism underlying upregulations described in {M}{C}{I} patients},
  journal = {Exp. Neurol.},
  year = {2009},
  volume = {217},
  number = {2},
  pages = {237--239},
  month = {Jun},
  note = {[DOI:\href{http://dx.doi.org/10.1016/j.expneurol.2009.03.013}{10.1016/j.expneurol.2009.03.013}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/19328200}{19328200}] }
}
@article{pmid19047044,
  author = {Kummer, M. P.  and Maruyama, H.  and Huelsmann, C.  and Baches, S.  and Weggen, S.  and Koo, E. H. },
  title = {{F}ormation of {P}mel17 amyloid is regulated by juxtamembrane metalloproteinase cleavage, and the resulting {C}-terminal fragment is a substrate for gamma-secretase},
  journal = {J. Biol. Chem.},
  year = {2009},
  volume = {284},
  number = {4},
  pages = {2296--2306},
  month = {Jan},
  abstract = {The formation of insoluble cross beta-sheet amyloid is pathologically associated with disorders such as Alzheimer, Parkinson, and Huntington diseases. One exception is the nonpathological amyloid derived from the protein Pmel17 within melanosomes to generate melanin pigment. Here we show that the formation of insoluble MalphaC intracellular fragments of Pmel17, which are the direct precursors to Pmel17 amyloid, depends on a novel juxtamembrane cleavage at amino acid position 583 between the furin-like proprotein convertase cleavage site and the transmembrane domain. The resulting Pmel17 C-terminal fragment is then processed by the gamma-secretase complex to release a short-lived intracellular domain fragment. Thus, by analogy to the Notch receptor, we designate this cleavage the S2 cleavage site, whereas gamma-secretase mediates proteolysis at the intramembrane S3 site. Substitutions or deletions at this S2 cleavage site, the use of the metalloproteinase inhibitor TAPI-2, as well as small interfering RNA-mediated knock-down of the metalloproteinases ADAM10 and 17 reduced the formation of insoluble Pmel17 fragments. These results demonstrate that the release of the Pmel17 ectodomain, which is critical for melanin amyloidogenesis, is initiated by S2 cleavage at a juxtamembrane position.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2629115}{PMC2629115}] [DOI:\href{http://dx.doi.org/10.1074/jbc.M808904200}{10.1074/jbc.M808904200}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/19047044}{19047044}] }
}
@article{pmid19005074,
  author = {Tamboli, I. Y.  and Prager, K.  and Thal, D. R.  and Thelen, K. M.  and Dewachter, I.  and Pietrzik, C. U.  and St George-Hyslop, P.  and Sisodia, S. S.  and De Strooper, B.  and Heneka, M. T.  and Filippov, M. A.  and Muller, U.  and van Leuven, F.  and Lutjohann, D.  and Walter, J. },
  title = {{L}oss of gamma-secretase function impairs endocytosis of lipoprotein particles and membrane cholesterol homeostasis},
  journal = {J. Neurosci.},
  year = {2008},
  volume = {28},
  number = {46},
  pages = {12097--12106},
  month = {Nov},
  abstract = {Presenilins (PSs) are components of the gamma-secretase complex that mediates intramembranous cleavage of type I membrane proteins. We show that gamma-secretase is involved in the regulation of cellular lipoprotein uptake. Loss of gamma-secretase function decreased endocytosis of low-density lipoprotein (LDL) receptor. The decreased uptake of lipoproteins led to upregulation of cellular cholesterol biosynthesis by increased expression of CYP51 and enhanced metabolism of lanosterol. Genetic deletion of PS1 or transgenic expression of PS1 mutants that cause early-onset Alzheimer's disease led to accumulation of gamma-secretase substrates and mistargeting of adaptor proteins that regulate endocytosis of the LDL receptor. Consistent with decreased endocytosis of these receptors, PS1 mutant mice have elevated levels of apolipoprotein E in the brain. Thus, these data demonstrate a functional link between two major genetic factors that cause early-onset and late-onset Alzheimer's disease.},
  note = {[DOI:\href{http://dx.doi.org/10.1523/JNEUROSCI.2635-08.2008}{10.1523/JNEUROSCI.2635-08.2008}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/19005074}{19005074}] }
}
@article{pmid18815619,
  author = {Seufert, S.  and Coras, R.  and Trankle, C.  and Zlotos, D. P.  and Blumcke, I.  and Tatenhorst, L.  and Heneka, M. T.  and Hahnen, E. },
  title = {{P}{P}{A}{R} {G}amma {A}ctivators: {O}ff-{T}arget {A}gainst {G}lioma {C}ell {M}igration and {B}rain {I}nvasion},
  journal = {PPAR Res},
  year = {2008},
  volume = {2008},
  pages = {513943},
  abstract = {Today, there is increasing evidence that PPARgamma agonists, including thiazolidinediones (TDZs) and nonthiazolidinediones, block the motility and invasiveness of glioma cells and other highly migratory tumor entities. However, the mechanism(s) by which PPARgamma activators mediate their antimigratory and anti-invasive properties remains elusive. This letter gives a short review on the debate and adds to the current knowledge by applying a PPARgamma inactive derivative of the TDZ troglitazone (Rezulin) which potently counteracts experimental glioma progression in a PPARgamma independent manner.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2542841}{PMC2542841}] [DOI:\href{http://dx.doi.org/10.1155/2008/513943}{10.1155/2008/513943}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/18815619}{18815619}] }
}
@article{pmid18793399,
  author = {Semmler, A.  and Hermann, S.  and Mormann, F.  and Weberpals, M.  and Paxian, S. A.  and Okulla, T.  and Schafers, M.  and Kummer, M. P.  and Klockgether, T.  and Heneka, M. T. },
  title = {{S}epsis causes neuroinflammation and concomitant decrease of cerebral metabolism},
  journal = {J Neuroinflammation},
  year = {2008},
  volume = {5},
  pages = {38},
  abstract = {Septic encephalopathy is a severe brain dysfunction caused by systemic inflammation in the absence of direct brain infection. Changes in cerebral blood flow, release of inflammatory molecules and metabolic alterations contribute to neuronal dysfunction and cell death.\\ To investigate the relation of electrophysiological, metabolic and morphological changes caused by SE, we simultaneously assessed systemic circulation, regional cerebral blood flow and cortical electroencephalography in rats exposed to bacterial lipopolysaccharide. Additionally, cerebral glucose uptake, astro- and microglial activation as well as changes of inflammatory gene transcription were examined by small animal PET using [18F]FDG, immunohistochemistry, and real time PCR.\\ While the systemic hemodynamic did not change significantly, regional cerebral blood flow was decreased in the cortex paralleled by a decrease of alpha activity of the electroencephalography. Cerebral glucose uptake was reduced in all analyzed neocortical areas, but preserved in the caudate nucleus, the hippocampus and the thalamus. Sepsis enhanced the transcription of several pro- and anti-inflammatory cytokines and chemokines including tumor necrosis factor alpha, interleukin-1 beta, transforming growth factor beta, and monocot chemoattractant protein 1 in the cerebrum. Regional analysis of different brain regions revealed an increase in ED1-positive microglia in the cortex, while total and neuronal cell counts decreased in the cortex and the hippocampus.\\ Together, the present study highlights the complexity of sepsis induced early impairment of neuronal metabolism and activity. Since our model uses techniques that determine parameters relevant to the clinical setting, it might be a useful tool to develop brain specific therapeutic strategies for human septic encephalopathy.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2553764}{PMC2553764}] [DOI:\href{http://dx.doi.org/10.1186/1742-2094-5-38}{10.1186/1742-2094-5-38}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/18793399}{18793399}] }
}
@article{pmid18725982,
  author = {Tatenhorst, L.  and Hahnen, E.  and Heneka, M. T. },
  title = {{P}eroxisome {P}roliferator-{A}ctivated {R}eceptors ({P}{P}{A}{R}s) as {P}otential {I}nducers of {A}ntineoplastic {E}ffects in {C}{N}{S} {T}umors},
  journal = {PPAR Res},
  year = {2008},
  volume = {2008},
  pages = {204514},
  abstract = {The peroxisome proliferator-activated receptors (PPARs) are ligand-inducible transcription factors which belong to the superfamily of nuclear hormone receptors. In recent years it turned out that natural as well as synthetic PPAR agonists exhibit profound antineoplastic as well as redifferentiation effects in tumors of the central nervous system (CNS). The molecular understanding of the underlying mechanisms is still emerging, with partially controverse findings reported by a number of studies dealing with the influence of PPARs on treatment of tumor cells in vitro. Remarkably, studies examining the effects of these drugs in vivo are just beginning to emerge. However, the agonists of PPARs, in particular the thiazolidinediones, seem to be promising candidates for new approaches in human CNS tumor therapy.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2517124}{PMC2517124}] [DOI:\href{http://dx.doi.org/10.1155/2008/204514}{10.1155/2008/204514}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/18725982}{18725982}] }
}
@article{pmid18645613,
  author = {Kummer, M. P.  and Heneka, M. T. },
  title = {{P}{P}{A}{R}s in {A}lzheimer's {D}isease},
  journal = {PPAR Res},
  year = {2008},
  volume = {2008},
  pages = {403896},
  abstract = {Peroxisome proliferator-activated receptors (PPARs) are well studied for their peripheral physiological and pathological impact, but they also play an important role for the pathogenesis of various disorders of the central nervous system (CNS) like multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer's, and Parkinson's disease. The observation that PPARs are able to suppress the inflammatory response in peripheral macrophages and in several models of human autoimmune diseases lead to the idea that PPARs might be beneficial for CNS disorders possessing an inflammatory component. The neuroinflammatory response during the course of Alzheimer's disease (AD) is triggered by the neurodegeneration and the deposition of the beta-amyloid peptide in extracellular plaques. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been considered to delay the onset and reduce the risk to develop Alzheimer's disease, while they also directly activate PPARgamma. This led to the hypothesis that NSAID protection in AD may be partly mediated by PPARgamma. Several lines of evidence have supported this hypothesis, using AD-related transgenic cellular and animal models. Stimulation of PPARgamma receptors by synthetic agonist (thiazolidinediones) inducing anti-inflammatory, anti-amyloidogenic, and insulin sensitising effects may account for the observed effects. Several clinical trials already revealed promising results using PPAR agonists, therefore PPARs represent an attractive therapeutic target for the treatment of AD.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2465016}{PMC2465016}] [DOI:\href{http://dx.doi.org/10.1155/2008/403896}{10.1155/2008/403896}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/18645613}{18645613}] }
}
@article{pmid18219484,
  author = {Winkeler, A.  and Waerzeggers, Y.  and Klose, A.  and Monfared, P.  and Thomas, A. V.  and Schubert, M.  and Heneka, M. T.  and Jacobs, A. H. },
  title = {{I}maging noradrenergic influence on amyloid pathology in mouse models of {A}lzheimer's disease},
  journal = {Eur. J. Nucl. Med. Mol. Imaging},
  year = {2008},
  volume = {35 Suppl 1},
  pages = {S107--113},
  month = {Mar},
  abstract = {Molecular imaging aims towards the non-invasive characterization of disease-specific molecular alterations in the living organism in vivo. In that, molecular imaging opens a new dimension in our understanding of disease pathogenesis, as it allows the non-invasive determination of the dynamics of changes on the molecular level. IMAGING OF AD CHARACTERISTIC CHANGES BY microPET: The imaging technology being employed includes magnetic resonance imaging (MRI) and nuclear imaging as well as optical-based imaging technologies. These imaging modalities are employed together or alone for disease phenotyping, development of imaging-guided therapeutic strategies and in basic and translational research. In this study, we review recent investigations employing positron emission tomography and MRI for phenotyping mouse models of Alzheimer's disease by imaging. We demonstrate that imaging has an important role in the characterization of mouse models of neurodegenerative diseases.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2755760}{PMC2755760}] [DOI:\href{http://dx.doi.org/10.1007/s00259-007-0710-0}{10.1007/s00259-007-0710-0}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/18219484}{18219484}] }
}
@article{pmid18045492,
  author = {Thees, C.  and Kaiser, M.  and Scholz, M.  and Semmler, A.  and Heneka, M. T.  and Baumgarten, G.  and Hoeft, A.  and Putensen, C. },
  title = {{C}erebral haemodynamics and carbon dioxide reactivity during sepsis syndrome},
  journal = {Crit Care},
  year = {2007},
  volume = {11},
  number = {6},
  pages = {R123},
  abstract = {Most patients with sepsis develop potentially irreversible cerebral dysfunctions. It is yet not clear whether cerebral haemodynamics are altered in these sepsis patients at all, and to what extent. We hypothesized that cerebral haemodynamics and carbon dioxide reactivity would be impaired in patients with sepsis syndrome and pathological electroencephalogram patterns.\\ After approval of the institutional ethics committee, 10 mechanically ventilated patients with sepsis syndrome and pathological electroencephalogram patterns underwent measurements of cerebral blood flow and jugular venous oxygen saturation before and after reduction of the arterial carbon dioxide partial pressure by 0.93 +/- 0.7 kPa iu by hyperventilation. The cerebral capillary closing pressure was determined from transcranial Doppler measurements of the arterial blood flow of the middle cerebral artery and the arterial pressure curve. A t test for matched pairs was used for statistical analysis (P < 0.05).\\ During stable mean arterial pressure and cardiac index, reduction of the arterial carbon dioxide partial pressure led to a significant increase of the capillary closing pressure from 25 +/- 11 mmHg to 39 +/- 15 mmHg (P < 0.001), with a consecutive decrease of blood flow velocity in the middle cerebral artery of 21.8 +/- 4.8\%/kPa (P < 0.001), of cerebral blood flow from 64 +/- 29 ml/100 g/min to 39 +/- 15 ml/100 g/min (P < 0.001) and of jugular venous oxygen saturation from 75 +/- 8\% to 67 +/- 14\% (P < 0.01).\\ In contrast to other experimental and clinical data, we observed no pathological findings in the investigated parameters of cerebral perfusion and oxygenation.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2246217}{PMC2246217}] [DOI:\href{http://dx.doi.org/10.1186/cc6185}{10.1186/cc6185}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/18045492}{18045492}] }
}
@article{pmid17805244,
  author = {Heneka, M. T.  and Landreth, G. E.  and Hull, M. },
  title = {{D}rug insight: effects mediated by peroxisome proliferator-activated receptor-gamma in {C}{N}{S} disorders},
  journal = {Nat Clin Pract Neurol},
  year = {2007},
  volume = {3},
  number = {9},
  pages = {496--504},
  month = {Sep},
  abstract = {The finding that activation of peroxisome proliferator-activated receptor-gamma (PPARgamma) suppresses inflammation in peripheral macrophages and in models of human autoimmune disease instigated the evaluation of this salutary action for the treatment of CNS disorders with an inflammatory component. The fact that NSAIDs delay the onset of and reduce the risk of developing Alzheimer's disease (AD), while also binding to and activating PPARgamma, led to the hypothesis that one dimension of NSAID protection in AD is mediated by PPARgamma. Several lines of evidence from experiments using AD-related transgenic cellular and animal models have supported this hypothesis. The capacity of PPARgamma agonists to elicit anti-inflammatory, anti-amyloidogenic and insulin-sensitizing effects might account for their observed protective effects. Several clinical trials employing PPARgamma agonists have yielded promising results, and further trials are in preparation. Positive outcomes following PPARgamma administration have been obtained in animal models of other neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis, both of which are associated with a considerable degree of neuroinflammation. Finally, activation of PPARgamma has been found to be protective in several models of multiple sclerosis. The verification of these findings in human cells prompted the initiation of clinical studies evaluating PPARgamma activation in patients with multiple sclerosis.},
  note = {[DOI:\href{http://dx.doi.org/10.1038/ncpneuro0586}{10.1038/ncpneuro0586}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/17805244}{17805244}] }
}
@article{pmid17569578,
  author = {Heneka, M. T.  and Landreth, G. E. },
  title = {{P}{P}{A}{R}s in the brain},
  journal = {Biochim. Biophys. Acta},
  year = {2007},
  volume = {1771},
  number = {8},
  pages = {1031--1045},
  month = {Aug},
  abstract = {The biology of peroxisome proliferator activated receptors (PPARs) in physiological and pathophysiological processes has been primarily studied in peripherial organs and tissues. Recently it became clear that PPARs play an important role for the pathogenesis of various disorders of the CNS. The finding that activation of PPARs, and in particular, the PPARgamma isoform, suppresses inflammation in peripherial macrophages and in models of human autoimmune disease, instigated the experimental evaluation of these salutary actions for several CNS disorders that have an inflammatory component. Activation of all PPAR isoforms, but especially of PPARgamma, has been found to be protective in murine in vitro and in vivo models of Multiple Sclerosis. The verification of these findings in human cells prompted the initiation of clinical studies evaluating PPARgamma activation in Multiple Sclerosis patients. Likewise, Alzheimer's disease has a prominent inflammatory component that arises in response to neurodegeneration and to extracellular deposition of beta-amyloid peptides. The fact that non steroidal anti-inflammatory drugs (NSAIDs) delay the onset and reduce the risk to develop Alzheimer's disease, while they also bind to and activate PPARgamma, led to the hypothesis that one dimension of NSAID protection in AD may be mediated by PPARgamma. Several lines of evidence from in vitro and in vivo studies have supported this hypothesis, using Alzheimer disease related transgenic cellular and animal models. The ability of PPAR agonists to elicit anti-amyloidogenic, anti-inflammatory and insulin sensitizing effects may account for the observed effects. A number of clinical trials employing PPAR agonists have yielded promising results and further trials are in preparation, which aim to delineate the exact mechanism of interaction. Animal models of other neurodegenerative diseases such as Parkinson's and Amyotrophic lateral sclerosis, both associated with a considerable degree of CNS inflammation, have been studied with a positive outcome. Yet it is not clear whether reduction of inflammation or additional mechanisms account for the observed neuroprotection. Less is known about the physiological role of PPARs for brain development, maintenance and function. Lesions from transgenic mouse models, however, provide evidence that PPARs may play pivotal roles for CNS development and function.},
  note = {[DOI:\href{http://dx.doi.org/10.1016/j.bbalip.2007.04.016}{10.1016/j.bbalip.2007.04.016}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/17569578}{17569578}] }
}
@article{pmid17532884,
  author = {Kummer, C.  and Winkeler, A.  and Dittmar, C.  and Bauer, B.  and Rueger, M. A.  and Rueckriem, B.  and Heneka, M. T.  and Vollmar, S.  and Wienhard, K.  and Fraefel, C.  and Heiss, W. D.  and Jacobs, A. H. },
  title = {{M}ultitracer positron emission tomographic imaging of exogenous gene expression mediated by a universal herpes simplex virus 1 amplicon vector},
  journal = {Mol Imaging},
  year = {2007},
  volume = {6},
  number = {3},
  pages = {181--192},
  abstract = {To develop efficient and safe gene therapy approaches, the herpes simplex virus type 1 thymidine kinase gene (HSV-1-tk) has been shown to function as a marker gene for the direct noninvasive in vivo localization of thymidine kinase (TK) expression by positron emission tomography (PET) using radiolabeled nucleoside analogues as specific TK substrates. Moreover, the gene encoding dopamine type 2 receptor (d2r) could be used as a PET marker gene using specific radiolabeled receptor binding compounds. Here we describe the quantitative colocalization of d2r and HSV-1-tk gene expression mediated from a universal HSV-1 amplicon vector in a subcutaneous human Gli36dEGFR glioma model by PET. The HSV-1 amplicon vector was constructed using a bicistronic gene cassette to contain (1) the d2r80A mutant, which is able to bind its ligand racloprid but unable to activate downstream signal transduction pathways, and (2) the tk39 mutant with enhanced enzymatic activity toward guanosine analogues fused to the green fluorescent protein gene (tk39gfp) serving as a marker gene in cell culture. After infection of human Gli36dEGFR glioma cells with the HSV-d2r80AIREStk39gfp (HSV-DITG) amplicon vector in cell culture, D2 receptor expression and its targeting to the cell surface were determined by Western blotting and immunolabeling. Vector application in vivo served for quantitative colocalization of d2r80A- and tk39gfp-derived PET signals employing the specific D2 receptor binding compound [(11)C]racloprid and the specific TK39 substrate 9-(4-[(18)F]fluoro-3-hydroxymethylbutyl)guanine. Our results demonstrate that for the range of gene expression studied in vivo, both enzymatic and receptor binding assays give comparable quantitative information on the level of vector-mediated gene expression in vivo. The d2r80A in combination with a specific binding compound passing the intact blood-brain barrier might be an alternative marker gene for the noninvasive assessment of vector-mediated gene expression in the brain using PET.},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/17532884}{17532884}] }
}
@article{pmid17420717,
  author = {Rueger, M. A.  and Kracht, L. W.  and Hilker, R.  and Thiel, A.  and Sobesky, J.  and Winkeler, A.  and Thomas, A. V.  and Heneka, M. T.  and Graf, R.  and Herholz, K.  and Heiss, W. D.  and Jacobs, A. H. },
  title = {{R}ole of in vivo imaging of the central nervous system for developing novel drugs},
  journal = {Q J Nucl Med Mol Imaging},
  year = {2007},
  volume = {51},
  number = {2},
  pages = {164--181},
  month = {Jun},
  abstract = {Over the past decade imaging technologies employed in clinical neurosciences have significantly advanced. Imaging is not only used for the diagnostic work-up of neurological disorders but also crucial to follow up on therapeutic efforts. Using disease-specific imaging parameters, as read-outs for the efficiency of individual therapies, has facilitated the development of various novel treatments for neurological disease. Here, we review various imaging technologies, such as cranial computed tomography (CT), magnetic resonance imaging (MRI) and spectroscopy (MRS), positron emission tomography (PET) and single-photon emission computed tomography (SPECT), with respect to their current applications in non-invasive disease phenotyping and the measurement of therapeutic outcomes in neurology. In particular, applications in neuro-oncology, Parkinson's disease, Alzheimer's disease, and cerebral ischemia are discussed. Non-invasive imaging provides further insights into the molecular pathophysiology of human diseases and facilitates the design and implementation of improved therapies.},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/17420717}{17420717}] }
}
@article{pmid17308112,
  author = {Jacobs, A. H.  and Rueger, M. A.  and Winkeler, A.  and Li, H.  and Vollmar, S.  and Waerzeggers, Y.  and Rueckriem, B.  and Kummer, C.  and Dittmar, C.  and Klein, M.  and Heneka, M. T.  and Herrlinger, U.  and Fraefel, C.  and Graf, R.  and Wienhard, K.  and Heiss, W. D. },
  title = {{I}maging-guided gene therapy of experimental gliomas},
  journal = {Cancer Res.},
  year = {2007},
  volume = {67},
  number = {4},
  pages = {1706--1715},
  month = {Feb},
  abstract = {To further develop gene therapy for patients with glioblastomas, an experimental gene therapy protocol was established comprising a series of imaging parameters for (i) noninvasive assessment of viable target tissue followed by (ii) targeted application of herpes simplex virus type 1 (HSV-1) amplicon vectors and (iii) quantification of treatment effects by imaging. We show that viable target tissue amenable for application of gene therapy vectors can be identified by multitracer positron emission tomography (PET) using 2-(18)F-fluoro-2-deoxy-D-glucose, methyl-(11)C-L-methionine, or 3'-deoxy-3'-(18)F-fluoro-L-thymidine ([(18)F]FLT). Targeted application of HSV-1 amplicon vectors containing two therapeutic genes with synergistic antitumor activity (Escherichia coli cytosine deaminase, cd, and mutated HSV-1 thymidine kinase, tk39, fused to green fluorescent protein gene, gfp) leads to an overall response rate of 68\%, with 18\% complete responses and 50\% partial responses. Most importantly, we show that the "tissue dose" of HSV-1 amplicon vector-mediated gene expression can be noninvasively assessed by 9-[4-(18)F-fluoro-3-(hydroxymethyl)butyl]guanine ([(18)F]FHBG) PET. Therapeutic effects could be monitored by PET with significant differences in [(18)F]FLT accumulation in all positive control tumors and 72\% in vivo transduced tumors (P = 0.01) as early as 4 days after prodrug therapy. For all stably and in vivo transduced tumors, cdIREStk39gfp gene expression as measured by [(18)F]FHBG-PET correlated with therapeutic efficiency as measured by [(18)F]FLT-PET. These data indicate that imaging-guided vector application with determination of tissue dose of vector-mediated gene expression and correlation to induced therapeutic effect using multimodal imaging is feasible. This strategy will help in the development of safe and efficient gene therapy protocols for clinical application.},
  note = {[DOI:\href{http://dx.doi.org/10.1158/0008-5472.CAN-06-2418}{10.1158/0008-5472.CAN-06-2418}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/17308112}{17308112}] }
}
@article{pmid17306796,
  author = {Semmler, A.  and Frisch, C.  and Debeir, T.  and Ramanathan, M.  and Okulla, T.  and Klockgether, T.  and Heneka, M. T. },
  title = {{L}ong-term cognitive impairment, neuronal loss and reduced cortical cholinergic innervation after recovery from sepsis in a rodent model},
  journal = {Exp. Neurol.},
  year = {2007},
  volume = {204},
  number = {2},
  pages = {733--740},
  month = {Apr},
  abstract = {Sepsis is a disease with a high and growing prevalence worldwide. Most studies on sepsis up to date have been focused on reduction of short-term mortality. This study investigates cognitive and neuroanatomical long-term consequences of sepsis in a rat model. Sepsis was induced in male Wistar rats weighing 250-300 g by an i.p. injection of bacterial lipopolysaccharide (LPS, 10 mg/kg). Three months after complete recovery from sepsis, animals showed memory deficits in the radial maze and changes in open field exploratory patterns but unaffected inhibitory avoidance learning. Behavioral findings were matched by sepsis-induced loss of neurons in the hippocampus and the prefrontal cortex on serial sections after NeuN-staining and reduced cholinergic innervation in the parietal cortex measured by immunoradiography of vesicular acetylcholine transporter (VAChT). Together these results suggest that sepsis can induce persistent behavioral and neuroanatomical changes and warrant studies of the neurological long-term consequences of sepsis in humans.},
  note = {[DOI:\href{http://dx.doi.org/10.1016/j.expneurol.2007.01.003}{10.1016/j.expneurol.2007.01.003}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/17306796}{17306796}] }
}
@article{pmid17222916,
  author = {Heneka, M. T.  and O'Banion, M. K. },
  title = {{I}nflammatory processes in {A}lzheimer's disease},
  journal = {J. Neuroimmunol.},
  year = {2007},
  volume = {184},
  number = {1-2},
  pages = {69--91},
  month = {Mar},
  abstract = {Generation and deposition of amyloid beta peptides and neurofibrillary tangle formation are key mechanisms involved in AD pathogenesis. Recent evidence suggests that inflammatory mechanisms represent a third component which, once initiated by degeneration, may significantly contribute to disease progression and chronicity. Various neuroinflammatory mediators including complement activators and inhibitors, chemokines, cytokines, radical oxygen species and inflammatory enzymes are generated and released by microglia, astrocytes and neurons. Degeneration of aminergic brain stem nuclei such as the locus ceruleus and the nucleus baslis of Meynert may facilitate the occurrence of inflammation in their respective projection areas given the antiinflammatory and neuroprotective action of their key products norepinephrine and acetylcholine. While inflammation has been thought to arise secondary to degeneration, recent experiments demonstrated that inflammatory mediators may stimulate APP processing by upregulation of beta secretase 1 and therefore are able to establish a vicious cycle. Despite the fact that some aspects of inflammation may even exert protective effects to bystander neurons, antiinflammatory treatment strategies should therefore be considered. Non-steroidal antiinflammatory drugs have been shown to reduce the risk and delay the onset to develop AD. However, the precise molecular mechanism underlying this effect is still being debated. Several mechanisms including inhibition of cyclooxygenase 2, gamma secretase or activation of the peroxisome proliferator activated receptor gamma may alone or, more likely, in concert account for the epidemiologically observed protection.},
  note = {[DOI:\href{http://dx.doi.org/10.1016/j.jneuroim.2006.11.017}{10.1016/j.jneuroim.2006.11.017}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/17222916}{17222916}] }
}
@article{pmid17151287,
  author = {Wahle, T.  and Thal, D. R.  and Sastre, M.  and Rentmeister, A.  and Bogdanovic, N.  and Famulok, M.  and Heneka, M. T.  and Walter, J. },
  title = {{G}{G}{A}1 is expressed in the human brain and affects the generation of amyloid beta-peptide},
  journal = {J. Neurosci.},
  year = {2006},
  volume = {26},
  number = {49},
  pages = {12838--12846},
  month = {Dec},
  abstract = {The beta-amyloid peptide (Abeta) is a major component of Alzheimer disease (AD)-associated senile plaques and is generated by sequential cleavage of the beta-amyloid precursor protein (APP) by beta-secretase (BACE1) and gamma-secretase. BACE1 cleaves APP at the N terminus of the Abeta domain, generating a membrane-bound C-terminal fragment (CTF-beta) that can be subsequently cleaved by gamma-secretase within the transmembrane domain to release Abeta. Because BACE1 initiates Abeta generation, it represents a potential target molecule to interfere with Abeta production in therapeutic strategies for AD. BACE1 interacts with Golgi-localized, gamma-ear-containing, ADP ribosylation factor-binding (GGA) proteins that are involved in the subcellular trafficking of BACE1. Here, we show that GGA1 is preferentially expressed in neurons of the human brain. GGA1 was also detected in activated microglia surrounding amyloid plaques in AD brains. Functional analyses with cultured cells demonstrate that GGA1 is implicated in the proteolytic processing of APP. Overexpression of GGA1 or a dominant-negative variant reduced cleavage of APP by BACE1 as indicated by a decrease in CTF-beta generation. Importantly, overexpression of GGA1 reduced, whereas RNAi-mediated suppression of GGA1 increased the secretion of Abeta. The modulation of APP processing by GGA1 is independent of a direct interaction of both proteins. Because total cellular activity of BACE1 was not affected by GGA1 expression, our data indicate that changes in the subcellular trafficking of BACE1 or other GGA1-dependent proteins contribute to changes in APP processing and Abeta generation. Thus, GGA proteins might be involved in the pathogenesis of AD.},
  note = {[DOI:\href{http://dx.doi.org/10.1523/JNEUROSCI.1982-06.2006}{10.1523/JNEUROSCI.1982-06.2006}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/17151287}{17151287}] }
}
@article{pmid16887936,
  author = {Grommes, C.  and Landreth, G. E.  and Sastre, M.  and Beck, M.  and Feinstein, D. L.  and Jacobs, A. H.  and Schlegel, U.  and Heneka, M. T. },
  title = {{I}nhibition of in vivo glioma growth and invasion by peroxisome proliferator-activated receptor gamma agonist treatment},
  journal = {Mol. Pharmacol.},
  year = {2006},
  volume = {70},
  number = {5},
  pages = {1524--1533},
  month = {Nov},
  abstract = {The peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear hormone receptor family, represents a possible new target in glioma therapy. Because PPARgamma plays a crucial role in regulation of insulin sensitivity, synthetic agonists are already in clinical use for type II diabetes treatment. Beyond these metabolic effects, PPARgamma agonists exhibit antineoplastic effects. In this study, we investigated the antineoplastic effects of the PPARgamma agonist pioglitazone in glioma cells. Pioglitazone reduced cellular viability of rat, human, and PPARgamma-overexpressing glioma cells in vitro in a time- and concentration-dependent manner. No antineoplastic effects were induced by pioglitazone in glioma cells overexpressing a PPARgamma mutant. Furthermore, proliferation was reduced by pioglitazone, as measured by Ki-67 immunoreactivity, in vitro. Continuous intracerebral infusion of pioglitazone into gliomas induced by intrastriatal injection of C6 cells reduced tumor volumes by 83\%. Oral administration of pioglitazone reduced tumor volumes by 76.9\%. Subsequent brain tissue analysis revealed induction of apoptotic cell death. Ki-67 expression and BrdU incorporation revealed a reduction of proliferation in vivo. Reduced invasion of C6 cells and lower matrix metalloproteinase 9 levels in vivo indicate pioglitazone-mediated reduction of invasion. Together, these data indicate that pioglitazone may be of potential use in treatment of malignant gliomas.},
  note = {[DOI:\href{http://dx.doi.org/10.1124/mol.106.022194}{10.1124/mol.106.022194}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/16887936}{16887936}] }
}
@article{pmid16877355,
  author = {Ambree, O.  and Leimer, U.  and Herring, A.  and Gortz, N.  and Sachser, N.  and Heneka, M. T.  and Paulus, W.  and Keyvani, K. },
  title = {{R}eduction of amyloid angiopathy and {A}beta plaque burden after enriched housing in {T}g{C}{R}{N}{D}8 mice: involvement of multiple pathways},
  journal = {Am. J. Pathol.},
  year = {2006},
  volume = {169},
  number = {2},
  pages = {544--552},
  month = {Aug},
  abstract = {Diversity and intensity of intellectual and physical activities seem to have an inverse relationship with the extent of cognitive decline in Alzheimer's disease (AD). To study the interaction between an active lifestyle and AD pathology, female TgCRND8 mice carrying human APPswe+ind were transferred into enriched housing. Four months of continuous and diversified environmental stimulation resulted in a significant reduction of beta-amyloid (Abeta) plaques and in a lower extent of amyloid angiopathy. Neither human amyloid precursor protein (APP) mRNA/protein levels nor the level of carboxy-terminal fragments of APP nor soluble Abeta content differed between both groups, making alterations in APP expression or processing unlikely as a cause of reduced Abeta deposition. Moreover, DNA microarray analysis revealed simultaneous down-regulation of proinflammatory genes as well as up-regulation of molecules involved in anti-inflammatory processes, proteasomal degradation, and cholesterol binding, possibly explaining reduced Abeta burden by lower aggregation and enhanced clearance of Abeta. Additionally, immunoblotting against F4/80 antigen and morphometric analysis of microglia (Mac-3) revealed significantly elevated microgliosis in the enriched brains, which suggests increased amyloid phagocytosis. In summary, this study demonstrates that the environment interacts with AD pathology at dif-ferent levels.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1698805}{PMC1698805}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/16877355}{16877355}] }
}
@article{pmid16837104,
  author = {Kalinin, S.  and Gavrilyuk, V.  and Polak, P. E.  and Vasser, R.  and Zhao, J.  and Heneka, M. T.  and Feinstein, D. L. },
  title = {{N}oradrenaline deficiency in brain increases beta-amyloid plaque burden in an animal model of {A}lzheimer's disease},
  journal = {Neurobiol. Aging},
  year = {2007},
  volume = {28},
  number = {8},
  pages = {1206--1214},
  month = {Aug},
  abstract = {Loss of Locus coeruleus (LC) noradrenergic (NA) neurons occurs in several neurodegenerative conditions including Alzheimer's disease (AD). In vitro and in vivo studies have shown that NA influences several features of AD disease including inflammation, neurodegeneration, and cognitive function. In the current study we tested if LC loss influenced beta amyloid (Abeta) plaque deposition. LC neuronal degeneration was induced in transgenic mice expressing mutant V717F human amyloid precursor protein (APP) by treatment with the selective neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine DSP4 (5mg/kg every 2 weeks beginning at age 3 months). At 9 months of age, when control mice show low amyloid load, DSP4-treated mice showed an approximately 5-fold increase in the average number of Abeta plaques. This was accompanied by an increase in the levels of APP C-terminal cleavage fragments. DSP4-treatment increased both microglial and astroglial activation. In vivo, DSP4-treatment decreased expression and activity of the Abeta degrading enzyme neprilysin, while in vitro NA increased phagocytosis of Abeta1-42 by microglia. These findings suggest that noradrenergic innervation from LC are needed to maintain adequate Abeta clearance, and therefore that LC degeneration could contribute to AD pathogenesis.},
  note = {[DOI:\href{http://dx.doi.org/10.1016/j.neurobiolaging.2006.06.003}{10.1016/j.neurobiolaging.2006.06.003}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/16837104}{16837104}] }
}
@article{pmid16636103,
  author = {Shaked, G. M.  and Kummer, M. P.  and Lu, D. C.  and Galvan, V.  and Bredesen, D. E.  and Koo, E. H. },
  title = {{A}beta induces cell death by direct interaction with its cognate extracellular domain on {A}{P}{P} ({A}{P}{P} 597-624)},
  journal = {FASEB J.},
  year = {2006},
  volume = {20},
  number = {8},
  pages = {1254--1256},
  month = {Jun},
  abstract = {Amyloid beta-peptide (Abeta) is postulated to play a central role in the pathogenesis of Alzheimer's disease. We recently proposed a pathway of Abeta-induced toxicity that is APP dependent and involves the facilitation of APP complex formation by Abeta. The APP-dependent component requires cleavage of APP at position 664 in the cytoplasmic domain, presumably by caspases or caspase-like proteases, with release of a potentially cytotoxic C31 peptide. In this study we show that Abeta interacted directly and specifically with membrane-bound APP to facilitate APP homo-oligomerization. Using chimeric APP molecules, this interaction was shown to take place between Abeta and its homologous sequence on APP. Consistent with this finding, we demonstrated that Abeta also facilitated the oligomerization of beta-secretase cleaved APP C-terminal fragment (C99). We found that the YENPTY domain in the APP cytoplasmic tail and contained within C31 is critical for this cell death pathway. Deletion or alanine- scanning mutagenesis through this domain significantly attenuated cell death apparently without affecting either APP dimerization or cleavage at position 664. This indicated that sequences within C31 are required after its release from APP. As the YENPTY domain has been shown to interact with a number of cytosolic adaptor molecules, it is possible that the interaction of APP, especially dimeric forms of APP, with these molecules contribute to cell death.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1847355}{PMC1847355}] [DOI:\href{http://dx.doi.org/10.1096/fj.05-5032fje}{10.1096/fj.05-5032fje}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/16636103}{16636103}] }
}
@article{pmid16472958,
  author = {Sastre, M.  and Klockgether, T.  and Heneka, M. T. },
  title = {{C}ontribution of inflammatory processes to {A}lzheimer's disease: molecular mechanisms},
  journal = {Int. J. Dev. Neurosci.},
  year = {2006},
  volume = {24},
  number = {2-3},
  pages = {167--176},
  abstract = {There is compelling evidence that Alzheimer's disease (AD) amyloid-beta (Abeta) deposition is associated with a local inflammatory response, which is initiated by the activation of microglia and the recruitment of astrocytes. These cells secrete a number of cytokines and neurotoxic products that may contribute to neuronal degeneration and cell death. It has been documented that long-term intake of non-steroidal anti-inflammatory drugs (NSAIDs) decrease the risk for developing AD and delay the onset of the disease. The mechanism behind these NSAIDs is still controversial and several hypotheses have been raised, including changes in the amyloid precursor protein (APP) metabolism, in Abeta aggregation and a decrease in inflammatory mediators. Recently, it was proposed that some NSAIDs might activate the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). PPAR-gamma belongs to a family of nuclear receptors that are able to regulate the transcription of pro-inflammatory molecules, such as iNOS. The activation of PPAR-gamma has been recently reported to reduce Abeta levels in cell culture and AD animal models. The implication of PPAR-gamma in the control of Abeta-induced inflammation suggests a new target for AD therapy and emphasize the contribution of neuroinflammatory mechanisms to the pathogenesis of AD.},
  note = {[DOI:\href{http://dx.doi.org/10.1016/j.ijdevneu.2005.11.014}{10.1016/j.ijdevneu.2005.11.014}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/16472958}{16472958}] }
}
@article{pmid16452658,
  author = {Heneka, M. T.  and Ramanathan, M.  and Jacobs, A. H.  and Dumitrescu-Ozimek, L.  and Bilkei-Gorzo, A.  and Debeir, T.  and Sastre, M.  and Galldiks, N.  and Zimmer, A.  and Hoehn, M.  and Heiss, W. D.  and Klockgether, T.  and Staufenbiel, M. },
  title = {{L}ocus ceruleus degeneration promotes {A}lzheimer pathogenesis in amyloid precursor protein 23 transgenic mice},
  journal = {J. Neurosci.},
  year = {2006},
  volume = {26},
  number = {5},
  pages = {1343--1354},
  month = {Feb},
  abstract = {Locus ceruleus (LC) degeneration and loss of cortical noradrenergic innervation occur early in Alzheimer's disease (AD). Although this has been known for several decades, the contribution of LC degeneration to AD pathogenesis remains unclear. We induced LC degeneration with N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (dsp4) in amyloid precursor protein 23 (APP23) transgenic mice with a low amyloid load. Then 6 months later the LC projection areas showed a robust elevation of glial inflammation along with augmented amyloid plaque deposits. Moreover, neurodegeneration and neuronal loss significantly increased. Importantly, the paraventricular thalamus, a nonprojection area, remained unaffected. Radial arm maze and social partner recognition tests revealed increased memory deficits while high-resolution magnetic resonance imaging-guided micro-positron emission tomography demonstrated reduced cerebral glucose metabolism, disturbed neuronal integrity, and attenuated acetylcholinesterase activity. Nontransgenic mice with LC degeneration were devoid of these alterations. Our data demonstrate that the degeneration of LC affects morphology, metabolism, and function of amyloid plaque-containing higher brain regions in APP23 mice. We postulate that LC degeneration substantially contributes to AD development.},
  note = {[DOI:\href{http://dx.doi.org/10.1523/JNEUROSCI.4236-05.2006}{10.1523/JNEUROSCI.4236-05.2006}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/16452658}{16452658}] }
}
@article{pmid16407166,
  author = {Sastre, M.  and Dewachter, I.  and Rossner, S.  and Bogdanovic, N.  and Rosen, E.  and Borghgraef, P.  and Evert, B. O.  and Dumitrescu-Ozimek, L.  and Thal, D. R.  and Landreth, G.  and Walter, J.  and Klockgether, T.  and van Leuven, F.  and Heneka, M. T. },
  title = {{N}onsteroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activation of {P}{P}{A}{R}gamma},
  journal = {Proc. Natl. Acad. Sci. U.S.A.},
  year = {2006},
  volume = {103},
  number = {2},
  pages = {443--448},
  month = {Jan},
  abstract = {Epidemiological evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the risk for Alzheimer's disease (AD). Certain NSAIDs can activate the peroxisome proliferator-activated receptor-gamma (PPARgamma), which is a nuclear transcriptional regulator. Here we show that PPARgamma depletion potentiates beta-secretase [beta-site amyloid precursor protein cleaving enzyme (BACE1)] mRNA levels by increasing BACE1 gene promoter activity. Conversely, overexpression of PPARgamma, as well as NSAIDs and PPARgamma activators, reduced BACE1 gene promoter activity. These results suggested that PPARgamma could be a repressor of BACE1. We then identified a PPARgamma responsive element (PPRE) in the BACE1 gene promoter. Mutagenesis of the PPRE abolished the binding of PPARgamma to the PPRE and increased BACE1 gene promoter activity. Furthermore, proinflammatory cytokines decreased PPARgamma gene transcription, and this effect was supressed by NSAIDs. We also demonstrate that in vivo treatment with PPARgamma agonists increased PPARgamma and reduced BACE1 mRNA and intracellular beta-amyloid levels. Interestingly, brain extracts from AD patients showed decreased PPARgamma expression and binding to PPRE in the BACE1 gene promoter. Our data strongly support a major role of PPARgamma in the modulation of amyloid-beta generation by inflammation and suggest that the protective mechanism of NSAIDs in AD involves activation of PPARgamma and decreased BACE1 gene transcription.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1326151}{PMC1326151}] [DOI:\href{http://dx.doi.org/10.1073/pnas.0503839103}{10.1073/pnas.0503839103}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/16407166}{16407166}] }
}
@article{pmid16300630,
  author = {Leuchtenberger, S.  and Kummer, M. P.  and Kukar, T.  and Czirr, E.  and Teusch, N.  and Sagi, S. A.  and Berdeaux, R.  and Pietrzik, C. U.  and Ladd, T. B.  and Golde, T. E.  and Koo, E. H.  and Weggen, S. },
  title = {{I}nhibitors of {R}ho-kinase modulate amyloid-beta ({A}beta) secretion but lack selectivity for {A}beta42},
  journal = {J. Neurochem.},
  year = {2006},
  volume = {96},
  number = {2},
  pages = {355--365},
  month = {Jan},
  abstract = {Certain non-steroidal anti-inflammatory drugs (NSAIDs) preferentially inhibit production of the amyloidogenic Abeta42 peptide, presumably by direct modulation of gamma-secretase activity. A recent report indicated that NSAIDs could reduce Abeta42 by inhibition of the small GTPase Rho, and a single inhibitor of Rho kinase (ROCK) mimicked the effects of Abeta42-lowering NSAIDs. To investigate whether Abeta42 reduction is a common property of ROCK inhibitors, we tested commercially available compounds in cell lines that were previously used to demonstrate the Abeta42-lowering activity of NSAIDs. Surprisingly, we found that two ROCK inhibitors reduced total Abeta secretion in a dose-dependent manner but showed no selectivity for Abeta42. In addition, ROCK inhibitors did not increase Abeta38 secretion in cell-based assays or reduce Abeta production in gamma-secretase in vitro assays, which are critical characteristics of Abeta42-lowering NSAIDs. The reduction in total Abeta levels by ROCK inhibitors was not accompanied by overall-changes in amyloid precursor protein processing. Targeting ROCK by expression of dominant-negative or constitutively active ROCK mutants failed to modulate Abeta secretion, indicating that ROCK inhibition may either be redundant or insufficient for Abeta reduction by ROCK inhibitors. Taken together, these results seem to exclude a mechanistic involvement of ROCK in the Abeta42-lowering activity of NSAIDs.},
  note = {[DOI:\href{http://dx.doi.org/10.1111/j.1471-4159.2005.03553.x}{10.1111/j.1471-4159.2005.03553.x}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/16300630}{16300630}] }
}
@article{pmid16212664,
  author = {Heneka, M. T.  and Sastre, M.  and Dumitrescu-Ozimek, L.  and Dewachter, I.  and Walter, J.  and Klockgether, T.  and Van Leuven, F. },
  title = {{F}ocal glial activation coincides with increased {B}{A}{C}{E}1 activation and precedes amyloid plaque deposition in {A}{P}{P}[{V}717{I}] transgenic mice},
  journal = {J Neuroinflammation},
  year = {2005},
  volume = {2},
  pages = {22},
  month = {Oct},
  abstract = {Inflammation is suspected to contribute to the progression and severity of neurodegeneration in Alzheimer's disease (AD). Transgenic mice overexpressing the london mutant of amyloid precursor protein, APP [V717I], robustly recapitulate the amyloid pathology of AD.\\ Early and late, temporal and spatial characteristics of inflammation were studied in APP [V717I] mice at 3 and 16 month of age. Glial activation and expression of inflammatory markers were determined by immunohistochemistry and RT-PCR. Amyloid deposition was assessed by immunohistochemistry, thioflavine S staining and western blot experiments. BACE1 activity was detected in brain lysates and in situ using the BACE1 activity kit from R&D Systems, Wiesbaden, Germany.\\ Foci of activated micro- and astroglia were already detected at age 3 months, before any amyloid deposition. Inflammation parameters comprised increased mRNA levels coding for interleukin-1beta, interleukin-6, major histocompatibility complex II and macrophage-colony-stimulating-factor-receptor. Foci of CD11b-positive microglia expressed these cytokines and were neighbored by activated astrocytes. Remarkably, beta-secretase (BACE1) mRNA, neuronal BACE1 protein at sites of focal inflammation and total BACE1 enzyme activity were increased in 3 month old APP transgenic mice, relative to age-matched non-transgenic mice. In aged APP transgenic mice, the mRNA of all inflammatory markers analysed was increased, accompanied by astroglial iNOS expression and NO-dependent peroxynitrite release, and with glial activation near almost all diffuse and senile Abeta deposits.\\ The early and focal glial activation, in conjunction with upregulated BACE1 mRNA, protein and activity in the presence of its substrate APP, is proposed to represent the earliest sites of amyloid deposition, likely evolving into amyloid plaques.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1274341}{PMC1274341}] [DOI:\href{http://dx.doi.org/10.1186/1742-2094-2-22}{10.1186/1742-2094-2-22}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/16212664}{16212664}] }
}
@article{pmid16210596,
  author = {Klotz, L.  and Schmidt, M.  and Giese, T.  and Sastre, M.  and Knolle, P.  and Klockgether, T.  and Heneka, M. T. },
  title = {{P}roinflammatory stimulation and pioglitazone treatment regulate peroxisome proliferator-activated receptor gamma levels in peripheral blood mononuclear cells from healthy controls and multiple sclerosis patients},
  journal = {J. Immunol.},
  year = {2005},
  volume = {175},
  number = {8},
  pages = {4948--4955},
  month = {Oct},
  abstract = {The peroxisome proliferator-activated receptor gamma (PPAR-gamma) belongs to a receptor superfamily of ligand-activated transcription factors involved in the regulation of metabolism and inflammation. Oral administration of PPAR-gamma agonists ameliorates the clinical course and histopathological features in experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis (MS), and PPAR-gamma agonist treatment of PBMCs from MS patients suppresses PHA-induced cell proliferation and cytokine secretion. These effects are pronounced when cells are preincubated with the PPAR-gamma agonists and reexposed at the time of stimulation, indicating a sensitizing effect. To characterize the mechanisms underlying this sensitizing effect, we analyzed PPAR-gamma expression in PMBCs of MS patients and healthy controls. Surprisingly, MS patients exhibited decreased PPAR-gamma levels compared with controls. PHA stimulation of PBMCs from healthy controls resulted in a significant loss of PPAR-gamma, which was prevented by in vitro preincubation of the cells or in vivo by long-term oral medication with the PPAR-gamma agonist pioglitazone. Differences in PPAR-gamma expression were accompanied by changes in PPAR-gamma DNA-binding activity, as preincubation with pioglitazone increased DNA binding of PPAR-gamma. Additionally, preincubation decreased NF-kappaB DNA-binding activity to control levels, whereas the inhibitory protein IkappaBalpha was increased. In MS patients, pioglitazone-induced increase in PPAR-gamma DNA-binding activity and decrease in NF-kappaB DNA-binding activity was only observed in the absence of an acute MS relapse. These results suggest that the sensitizing effect observed in the preincubation experiments is mediated by prevention of inflammation-induced suppression of PPAR-gamma expression with consecutive increase in PPAR-gamma DNA-binding activity.},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/16210596}{16210596}] }
}
@article{pmid16122904,
  author = {Semmler, A.  and Okulla, T.  and Sastre, M.  and Dumitrescu-Ozimek, L.  and Heneka, M. T. },
  title = {{S}ystemic inflammation induces apoptosis with variable vulnerability of different brain regions},
  journal = {J. Chem. Neuroanat.},
  year = {2005},
  volume = {30},
  number = {2-3},
  pages = {144--157},
  month = {Oct},
  abstract = {During severe sepsis several immunological defence mechanisms initiate a cascade of inflammatory events leading to multi-organ failure including septic encephalopathy and ultimately death. To assess the reaction and participation of parenchymal brain cells during endotoxaemia, the present study evaluates micro- and astroglial activation, expression of the inducible nitric oxide synthase (iNOS) pro- and antiapoptotic protein levels Bax and Bcl-2, and apoptosis. Male Wistar rats received 10 mg/kg lipopolysaccharide (LPS) or vehicle intraperitoneally and were sacrificed for brain collection at 4, 8 or 24 h after induction of experimental sepsis. One group of animals received 10 mg/kg of the NOS inhibitor N-monomethyl-L-arginine (L-NMMA) intraperitoneally 1 day before and during the experiment. Immunohistochemical evaluation revealed a sepsis-induced, time-dependent increase in the immunoreactivity of iNOS, glial fibrillary acidic protein (GFAP) and activated microglia (ED-1), paralleled by a time-dependent increase of apoptotic brain cells marked by terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL), an increase of Bax-positive cells and a decrease of Bcl-2-positive cells. Evaluation of different brain regions revealed that the hippocampus is the most vulnerable region during experimental sepsis. iNOS-inhibition with L-NMMA significantly reduced the number of apoptotic cells in hippocampus, midbrain and cerebellum. In addition, it reduced the increase of the proapoptotic protein Bax in all examined brain regions and reduced the decrease of Bcl-2-positive cells in the hippocampus. We therefore conclude, that peripheral inflammation leads to a profound glial activation, the generation of nitric oxide and changes of Bax and Bcl-2 protein regulation critical for apoptosis.},
  note = {[DOI:\href{http://dx.doi.org/10.1016/j.jchemneu.2005.07.003}{10.1016/j.jchemneu.2005.07.003}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/16122904}{16122904}] }
}
@article{pmid16120782,
  author = {Schutz, B.  and Reimann, J.  and Dumitrescu-Ozimek, L.  and Kappes-Horn, K.  and Landreth, G. E.  and Schurmann, B.  and Zimmer, A.  and Heneka, M. T. },
  title = {{T}he oral antidiabetic pioglitazone protects from neurodegeneration and amyotrophic lateral sclerosis-like symptoms in superoxide dismutase-{G}93{A} transgenic mice},
  journal = {J. Neurosci.},
  year = {2005},
  volume = {25},
  number = {34},
  pages = {7805--7812},
  month = {Aug},
  abstract = {Amyotrophic lateral sclerosis (ALS) represents a fatal neurodegenerative disorder characterized by progressive death of the upper and lower motor neurons. Because accompanying inflammation may interact with and promote neurodegeneration, anti-inflammatory treatment strategies are being evaluated. Because peroxisome proliferator-activated receptor gamma (PPARgamma) agonists act as potent anti-inflammatory drugs, we tested whether superoxide dismutase (SOD1)-G93A transgenic mice, a mouse model of ALS, benefit from oral treatment with the PPARgamma agonist pioglitazone (Pio). Pio-treated transgenic mice revealed improved muscle strength and body weight, exhibited a delayed disease onset, and survived significantly longer than nontreated SOD1-G93A mice. Quantification of motor neurons of the spinal cord at day 90 revealed complete neuroprotection by Pio, whereas nontreated SOD1-G93A mice had lost 30\% of motor neurons. This was paralleled by preservation of the median fiber diameter of the quadriceps muscle, indicating not only morphological but also functional protection of motor neurons by Pio. Activated microglia were significantly reduced at sites of neurodegeneration in Pio-treated SOD1-G93A mice, as were the protein levels of cyclooxygenase 2 and inducible nitric oxide synthase. Interestingly, mRNA levels of the suppressor of cytokine signaling 1 and 3 genes were increased by Pio, whereas both the mRNA and protein levels of endogenous mouse SOD1 and of transgenic human SOD1 remained unaffected.},
  note = {[DOI:\href{http://dx.doi.org/10.1523/JNEUROSCI.2038-05.2005}{10.1523/JNEUROSCI.2038-05.2005}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/16120782}{16120782}] }
}
@article{pmid15817521,
  author = {Heneka, M. T.  and Sastre, M.  and Dumitrescu-Ozimek, L.  and Hanke, A.  and Dewachter, I.  and Kuiperi, C.  and O'Banion, K.  and Klockgether, T.  and Van Leuven, F.  and Landreth, G. E. },
  title = {{A}cute treatment with the {P}{P}{A}{R}gamma agonist pioglitazone and ibuprofen reduces glial inflammation and {A}beta1-42 levels in {A}{P}{P}{V}717{I} transgenic mice},
  journal = {Brain},
  year = {2005},
  volume = {128},
  number = {Pt 6},
  pages = {1442--1453},
  month = {Jun},
  abstract = {Neuritic plaques in the brain of Alzheimer's disease patients are characterized by beta-amyloid deposits associated with a glia-mediated inflammatory response. Non-steroidal anti-inflammatory drug (NSAID) therapy reduces Alzheimer's disease risk and ameliorates microglial reactivity in Alzheimer's disease brains; however, the molecular mechanisms subserving this effect are not yet clear. Since several NSAIDs bind to and activate the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) which acts to inhibit the expression of proinflammatory genes, this receptor appears a good candidate to mediate the observed anti-inflammatory effects. Recent data in vitro suggested that NSAIDs negatively regulate microglial activation and immunostimulated amyloid precursor protein processing via PPARgamma activation. We report that an acute 7 day oral treatment of 10-month-old APPV717I mice with the PPARgamma agonist pioglitazone or the NSAID ibuprofen resulted in a reduction in the number of activated microglia and reactive astrocytes in the hippocampus and cortex. Drug treatment reduced the expression of the proinflammatory enzymes cyclooxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS). In parallel to the suppression of inflammatory markers, pioglitazone and ibuprofen treatment decreased beta-secretase-1 (BACE1) mRNA and protein levels. Importantly, we observed a significant reduction of the total area and staining intensity of Abeta1-42-positive amyloid deposits in the hippocampus and cortex. Additionally, animals treated with pioglitazone revealed a 27\% reduction in the levels of soluble Abeta1-42 peptide. These findings demonstrate that anti-inflammatory drugs can act rapidly to inhibit inflammatory responses in the brain and negatively modulate amyloidogenesis.},
  note = {[DOI:\href{http://dx.doi.org/10.1093/brain/awh452}{10.1093/brain/awh452}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/15817521}{15817521}] }
}
@article{pmid15674397,
  author = {Rueger, M. A.  and Winkeler, A.  and Miletic, H.  and Kaestle, C.  and Richter, R.  and Schneider, G.  and Hilker, R.  and Heneka, M. T.  and Ernestus, R. I.  and Hampl, J. A.  and Fraefel, C.  and Jacobs, A. H. },
  title = {{V}ariability in infectivity of primary cell cultures of human brain tumors with {H}{S}{V}-1 amplicon vectors},
  journal = {Gene Ther.},
  year = {2005},
  volume = {12},
  number = {7},
  pages = {588--596},
  month = {Apr},
  abstract = {We investigated the variability in infectivity of cells in primary brain tumor samples from different patients using an HSV-1 amplicon vector. We studied the infectivity of HSV-1 amplicon vectors in tumor samples derived from neurosurgical resections of 20 patients. Cells were infected with a definite amount of HSV-1 amplicon vector HSV-GFP. Transduction efficiency in primary tumor cell cultures was compared to an established human glioma line. Moreover, duration of transgene expression was monitored in different tumor cell types. All primary cell cultures were infectable with HSV-GFP with variable transduction efficiencies ranging between 3.0 and 42.4\% from reference human Gli36 Delta EGFR glioma cells. Transduction efficiency was significantly greater in anaplastic gliomas and meningiomas (26.7+/-17.4\%) compared to more malignant tumor types (glioblastomas, metastases; 11.2+/-8.5\%; P=0.05). To further investigate the possible underlying mechanism of this variability, nectin-1/HevC expression was analyzed and was found to contribute, at least in part, to this variability in infectability. The tumor cells expressed the exogenous gene for 7 to 61 days with significant shorter expression in glioblastomas (18+/-13 d) compared to anaplastic gliomas (42+/-24 d; P<0.05). Interindividual variability of infectivity by HSV-1 virions might explain, at least in part, why some patients enrolled in gene therapy for glioblastoma in the past exhibited a sustained response to HSV-1-based gene- and virus therapy. Infectivity of primary tumor samples from respective patients should be tested to enable the development of efficient and safe herpes vector-based gene and virus therapy for clinical application.},
  note = {[DOI:\href{http://dx.doi.org/10.1038/sj.gt.3302462}{10.1038/sj.gt.3302462}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/15674397}{15674397}] }
}
@article{pmid15665144,
  author = {Grommes, C.  and Landreth, G. E.  and Schlegel, U.  and Heneka, M. T. },
  title = {{T}he nonthiazolidinedione tyrosine-based peroxisome proliferator-activated receptor gamma ligand {G}{W}7845 induces apoptosis and limits migration and invasion of rat and human glioma cells},
  journal = {J. Pharmacol. Exp. Ther.},
  year = {2005},
  volume = {313},
  number = {2},
  pages = {806--813},
  month = {May},
  abstract = {Despite new approaches, treatment options for malignant gliomas are still limited, calling for further development of therapeutic strategies. The peroxisome proliferator-activated receptor (PPAR)gamma, a member of the nuclear hormone receptor family, represents a possible new target for neoplastic therapies. Synthetic PPARgamma agonists were developed and are already in clinical use for the treatment of type II diabetes, since PPARgamma plays a crucial role in lipid metabolism and regulation of insulin sensitivity. Beyond these metabolic effects, PPARgamma agonists exhibit antineoplastic effects in various malignant tumor cells. Here, we investigated the antineoplastic effects of the nonthiazolidinedione tyrosine-based PPARgamma ligand (S)-2-(1-carboxy-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}ethylamino)benzoic acid methyl ester (GW7845) in rat and human glioma cells. GW7845 reduced cellular viability of rat C6 glioma and human glioma cells in a time-dependent manner. Analysis of GW7845-treated tumor cells revealed induction of apoptotic cell death as determined by terminal deoxynucleotidyl transferase dUTP nick-end labeling staining and cleaved caspase-3 activation. Furthermore, GW7845 reduced proliferation of C6 glioma cells as measured by Ki-67 immunore-activity. There was also a reduction of migration and invasion, assessed by Boyden chamber and spheroid experiments. Together, these data indicate that the PPARgamma agonist GW7845 may be of potential use in treatment of malignant gliomas.},
  note = {[DOI:\href{http://dx.doi.org/10.1124/jpet.104.078972}{10.1124/jpet.104.078972}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/15665144}{15665144}] }
}
@article{pmid15285804,
  author = {Lacombe, P.  and Mathews, P. M.  and Schmidt, S. D.  and Breidert, T.  and Heneka, M. T.  and Landreth, G. E.  and Feinstein, D. L.  and Galea, E. },
  title = {{E}ffect of anti-inflammatory agents on transforming growth factor beta over-expressing mouse brains: a model revised},
  journal = {J Neuroinflammation},
  year = {2004},
  volume = {1},
  number = {1},
  pages = {11},
  month = {Jul},
  abstract = {BACKGROUND: The over-expression of transforming growth factor beta-1(TGF-beta1) has been reported to cause hydrocephalus, glia activation, and vascular amyloidbeta (Abeta) deposition in mouse brains. Since these phenomena partially mimic the cerebral amyloid angiopathy (CAA) concomitant to Alzheimer's disease, the findings in TGF-beta1 over-expressing mice prompted the hypothesis that CAA could be caused or enhanced by the abnormal production of TGF-beta1. This idea was in accordance with the view that chronic inflammation contributes to Alzheimer's disease, and drew attention to the therapeutic potential of anti-inflammatory drugs for the treatment of Abeta-elicited CAA. We thus studied the effect of anti-inflammatory drug administration in TGF-beta1-induced pathology. METHODS: Two-month-old TGF-beta1 mice and littermate controls were orally administered pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, or ibuprofen, a non steroidal anti-inflammatory agent, for two months. Glia activation was assessed by immunohistochemistry and western blot analysis; Abeta precursor protein (APP) by western blot analysis; Abeta deposition by immunohistochemistry, thioflavin-S staining and ELISA; and hydrocephalus by measurements of ventricle size on autoradiographies of brain sections. Results are expressed as means +/- SD. Data comparisons were carried with the Student's T test when two groups were compared, or ANOVA analysis when more than three groups were analyzed. RESULTS: Animals displayed glia activation, hydrocephalus and a robust thioflavin-S-positive vascular deposition. Unexpectedly, these deposits contained no Abeta or serum amyloid P component, a common constituent of amyloid deposits. The thioflavin-S-positive material thus remains to be identified. Pioglitazone decreased glia activation and basal levels of Abeta42- with no change in APP contents - while it increased hydrocephalus, and had no effect on the thioflavin-S deposits. Ibuprofen mimicked the reduction of glia activation caused by pioglitazone and the lack of effect on the thioflavin-S-labeled deposits. CONCLUSIONS: i) TGF-beta1 over-expressing mice may not be an appropriate model of Abeta-elicited CAA; and ii) pioglitazone has paradoxical effects on TGF-beta1-induced pathology suggesting that anti-inflammatory therapy may reduce the damage resulting from active glia, but not from vascular alterations or hydrocephalus. Identification of the thioflavin-S-positive material will facilitate the full appraisal of the clinical implication of the effects of anti-inflammatory drugs, and provide a more thorough understanding of TGF-beta1 actions in brain.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC500868}{PMC500868}] [DOI:\href{http://dx.doi.org/10.1186/1742-2094-1-11}{10.1186/1742-2094-1-11}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/15285804}{15285804}] }
}
@article{pmid15285799,
  author = {Pershadsingh, H. A.  and Heneka, M. T.  and Saini, R.  and Amin, N. M.  and Broeske, D. J.  and Feinstein, D. L. },
  title = {{E}ffect of pioglitazone treatment in a patient with secondary multiple sclerosis},
  journal = {J Neuroinflammation},
  year = {2004},
  volume = {1},
  number = {1},
  pages = {3},
  month = {Apr},
  abstract = {BACKGROUND: Ligands of the peroxisome proliferator-activated receptor-gamma (PPARgamma) induce apoptosis in activated T-lymphocytes and exert anti-inflammatory effects in glial cells. Preclinical studies have shown that the thiazolidinedione pioglitazone, an FDA-approved PPARgamma agonist used to treat type 2 diabetes, delays the onset and reduces the severity of clinical symptoms in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS). We therefore tested the safety and therapeutic potential of oral pioglitazone in a patient with secondary MS. CASE PRESENTATION: The rationale and risks of taking pioglitazone were carefully explained to the patient, consent was obtained, and treatment was initiated at 15 mg per day p.o. and then increased by 15 mg biweekly to 45 mg per day p.o. for the duration of the treatment. Safety was assessed by measurements of metabolic profiles, blood pressure, and edema; effects on clinical symptoms were assessed by measurement of cognition, motor function and strength, and MRI. Within 4 weeks the patient exhibited increased appetite, cognition and attention span. After 12 months treatment, body weight increased from 27.3 to 35.9 kg (32\%) and maintained throughout the duration of the study. Upper extremity strength and coordination improved, and increased fine coordination was noted unilaterally after 8 months and bilaterally after 15 months. After 8 months therapy, the patient demonstrated improvement in orientation, short-term memory, and attention span. MRIs carried out after 10 and 18 months of treatment showed no perceptible change in overall brain atrophy, extent of demyelination, or in Gd-enhancement. After 3.0 years on pioglitazone, the patient continues to be clinically stable, with no adverse events. CONCLUSIONS: In a patient with secondary progressive MS, daily treatment with 45 mg p.o. pioglitazone for 3 years induced apparent clinical improvement without adverse events. Pioglitazone should therefore be considered for further testing of therapeutic potential in MS patients.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC483056}{PMC483056}] [DOI:\href{http://dx.doi.org/10.1186/1742-2094-1-3}{10.1186/1742-2094-1-3}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/15285799}{15285799}] }
}
@article{pmid15231248,
  author = {Grommes, C.  and Landreth, G. E.  and Heneka, M. T. },
  title = {{A}ntineoplastic effects of peroxisome proliferator-activated receptor gamma agonists},
  journal = {Lancet Oncol.},
  year = {2004},
  volume = {5},
  number = {7},
  pages = {419--429},
  month = {Jul},
  abstract = {Peroxisome proliferator-activated receptors (PPAR) are members of a superfamily of nuclear hormone receptors. Activation of PPAR isoforms elicits both antineoplastic and anti-inflammatory effects in several types of mammalian cells. PPARs are ligand-activated transcription factors and have a subfamily of three different isoforms: PPAR alpha, PPAR gamma, and PPAR beta/delta. All isoforms heterodimerise with the 9-cis-retinoic acid receptor RXR, and play an important part in the regulation of several metabolic pathways, including lipid biosynthesis and glucose metabolism. Endogenous ligands of PPAR gamma include long-chain polyunsaturated fatty acids, eicosanoid derivates, and oxidised lipids. Newly developed synthetic ligands include thiazolidinediones-a group of potent PPAR gamma agonists and antidiabetic agents. Here, we review PPAR gamma-induced antineoplastic signalling pathways, and summarise the antineoplastic effects of PPAR gamma agonists in different cancer cell lines, animal models, and clinical trials.},
  note = {[DOI:\href{http://dx.doi.org/10.1016/S1470-2045(04)01509-8}{10.1016/S1470-2045(04)01509-8}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/15231248}{15231248}] }
}
@article{pmid14690537,
  author = {Dehmer, T.  and Heneka, M. T.  and Sastre, M.  and Dichgans, J.  and Schulz, J. B. },
  title = {{P}rotection by pioglitazone in the {M}{P}{T}{P} model of {P}arkinson's disease correlates with {I} kappa {B} alpha induction and block of {N}{F} kappa {B} and i{N}{O}{S} activation},
  journal = {J. Neurochem.},
  year = {2004},
  volume = {88},
  number = {2},
  pages = {494--501},
  month = {Jan},
  abstract = {Inflammation has been implicated in the pathogenesis of Parkinson's disease (PD). In the chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD, inducible NO synthase (iNOS) derived nitric oxide (NO) is an important mediator of dopaminergic cell death. Ligands of the peroxisome proliferator-activated receptor (PPAR) exert anti-inflammatory effects. We here investigated whether pioglitazone, a PPARgamma agonist, protected mice from MPTP-induced dopaminergic cell loss, glial activation, and loss of catecholamines in the striatum. As shown by western blot, PPARgamma was expressed in the striatum and the substantia nigra of vehicle- and MPTP-treated mice. Oral administration of 20 mg/(kg day) of pioglitazone protected tyrosine hydroxylase (TH)-positive substantia nigra neurons from death induced by 5 x 30 mg/kg MPTP. However, the decrease of dopamine in the striatum was only partially prevented. In mice treated with pioglitazone, there were a reduced activation of microglia, reduced induction of iNOS-positive cells and less glial fibrillary acidic protein positive cells in both striatum and substantia nigra pars compacta. In addition, treatment with pioglitazone almost completely blocked staining of TH-positive neurons for nitrotyrosine, a marker of NO-mediated cell damage. Because an increase in inhibitory protein-kappa-Balpha (IkappaBalpha) expression and inhibition of translocation of the nuclear factor kappaB (NFkappaB) subunit p65 to the nucleus in dopaminergic neurons, glial cells and astrocytes correlated with the protective effects of pioglitazone, our results suggest that pioglitazone sequentially acts through PPARgamma activation, IkappaBalpha induction, block of NFkappaB activation, iNOS induction and NO-mediated toxicity. In conclusion, treatment with pioglitazone may offer a treatment opportunity in PD to slow the progression of disease that is mediated by inflammation.},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/14690537}{14690537}] }
}
@article{pmid14690498,
  author = {Schmitz, A.  and Schneider, A.  and Kummer, M. P.  and Herzog, V. },
  title = {{E}ndoplasmic reticulum-localized amyloid beta-peptide is degraded in the cytosol by two distinct degradation pathways},
  journal = {Traffic},
  year = {2004},
  volume = {5},
  number = {2},
  pages = {89--101},
  month = {Feb},
  abstract = {The paradigm of endoplasmic reticulum (ER)-associated degradation (ERAD) holds that misfolded secretory and membrane proteins are translocated back to the cytosol and degraded by the proteasome in a coupled process. Analyzing the degradation of ER-localized amyloid beta-peptide (Abeta), we found a divergence from this general model. Cell-free reconstitution of the export in biosynthetically loaded ER-derived brain microsomes showed that the export was mediated by the Sec61p complex and required a cytosolic factor but was independent of ATP. In contrast to the ERAD substrates known so far, the exported Abeta was degraded by both, a proteasome-dependent and a proteasome-independent pathway. RNA interference experiments in Abeta-transfected cells identified the protease of the proteasome-independent pathway as insulin-degrading enzyme (IDE). The IDE-mediated clearance mechanism for ER-localized Abeta represents an as yet unknown type of ERAD which is not entirely dependent on the proteasome.},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/14690498}{14690498}] }
}
@article{pmid14657213,
  author = {Schmidt, S.  and Moric, E.  and Schmidt, M.  and Sastre, M.  and Feinstein, D. L.  and Heneka, M. T. },
  title = {{A}nti-inflammatory and antiproliferative actions of {P}{P}{A}{R}-gamma agonists on {T} lymphocytes derived from {M}{S} patients},
  journal = {J. Leukoc. Biol.},
  year = {2004},
  volume = {75},
  number = {3},
  pages = {478--485},
  month = {Mar},
  abstract = {Peroxisomal proliferator-activated receptors (PPARs) belong to a nuclear receptor superfamily of ligand-activated transcription factors. The PPAR-gamma isoform is expressed in human T lymphocytes, and oral administration of PPAR-gamma agonists ameliorates the clinical course and histopathological features in experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis, suggesting a potential role for PPAR-gamma agonists in the treatment of autoimmune diseases. To assess a potential therapeutic role of PPAR-gamma agonists in multiple sclerosis, we compared the immunomodulatory effects of the thiazolidinedione (TZD) drugs pioglitazone (PIO) and ciglitazone and the non-TZD PPAR-gamma agonist GW347845 on human T leukemia cells (Jurkat cells) and phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMCs) derived from 21 multiple sclerosis patients and 12 healthy donors. PIO, ciglitazone, and GW347845 suppressed PHA-induced T cell proliferation by 40-50\% and secretion of interferon-gamma and tumor necrosis factor alpha, by 30-50\%. Inhibition of proliferation was increased to approximately 80\% and that of proinflammatory cytokine secretion, to 80-90\% when PBMCs were first preincubated with PPAR-gamma agonists and re-exposed at the time of PHA stimulation, indicating a sensitizing effect of PPAR-gamma agonists. Inhibition of proliferation was also observed in the tetanus toxoid-specific T cell line KHS.TT2, albeit to a lesser extent. The antiproliferative effects of PIO and GW347845 were accompanied by a decrease of cell viability. Electron microscopy and Western blot analysis revealed DNA condensation and down-regulation of bcl-2, suggesting the induction of apoptosis in activated T lymphocytes. In summary, the data support the potential use of PPAR-gamma agonists as immunomodulatory, therapeutic agents for autoimmune diseases.},
  note = {[DOI:\href{http://dx.doi.org/10.1189/jlb.0803402}{10.1189/jlb.0803402}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/14657213}{14657213}] }
}
@article{pmid14597101,
  author = {Pedraza, C. E.  and Baltrons, M. A.  and Heneka, M. T.  and Garcia, A. },
  title = {{I}nterleukin-1 beta and lipopolysaccharide decrease soluble guanylyl cyclase in brain cells: {N}{O}-independent destabilization of protein and {N}{O}-dependent decrease of m{R}{N}{A}},
  journal = {J. Neuroimmunol.},
  year = {2003},
  volume = {144},
  number = {1-2},
  pages = {80--90},
  month = {Nov},
  abstract = {We previously showed that soluble guanylyl cyclase (sGC) is down-regulated in astroglial cells after exposure to LPS. Here, we show that this effect is not mediated by released IL-1beta but that this cytokine is also able to decrease NO-dependent cGMP accumulation in a time- and concentration-dependent manner. The effect of IL-1beta is receptor-mediated, mimicked by tumor necrosis factor-alpha and involves a decrease in sGC activity and protein. IL-1beta and LPS decrease the half-life of the sGC beta1 subunit by a NO-independent but transcription- and translation-dependent mechanism. Additionally, both agents induce a NO-dependent decrease of sGC subunit mRNA. Decreased sGC subunit protein and mRNA levels are also observed in adult rat brain after focal injection of IL-1beta or LPS.},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/14597101}{14597101}] }
}
@article{pmid14586007,
  author = {Sastre, M.  and Dewachter, I.  and Landreth, G. E.  and Willson, T. M.  and Klockgether, T.  and van Leuven, F.  and Heneka, M. T. },
  title = {{N}onsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase},
  journal = {J. Neurosci.},
  year = {2003},
  volume = {23},
  number = {30},
  pages = {9796--9804},
  month = {Oct},
  abstract = {Long-term treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk for Alzheimer's disease (AD). To determine the mechanisms by which inflammation affects AD and how NSAIDs protect against it, we stimulated neuroblastoma cells stably transfected with amyloid precursor protein (APP) with proinflammatory cytokines, which increased the secretion of amyloid-beta and APP ectodomain. Addition of ibuprofen, indomethacin, peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists, or cotransfection with PPARgamma cDNA reversed this effect. The inhibitory action of ibuprofen and indomethacin was suppressed by PPARgamma antagonists. Finally, we observed that the mRNA levels, expression, and enzymatic activity of beta-secretase were increased by immunostimulation and normalized by NSAIDs. In conclusion, proinflammatory cytokines activate beta-secretase, and NSAIDs inhibit this effect through PPARgamma.},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/14586007}{14586007}] }
}
@article{pmid14514020,
  author = {Galea, E.  and Heneka, M. T.  and Dello Russo, C.  and Feinstein, D. L. },
  title = {{I}ntrinsic regulation of brain inflammatory responses},
  journal = {Cell. Mol. Neurobiol.},
  year = {2003},
  volume = {23},
  number = {4-5},
  pages = {625--635},
  month = {Oct},
  abstract = {It is now well accepted that inflammatory responses in brain contribute to the genesis and evolution of damage in neurological diseases, trauma, and infection. Inflammatory mediators including cytokines, cell adhesion molecules, and reactive oxygen species including NO are detected in human brain and its animal models, and interventions that reduce levels or expression of these agents provide therapeutic benefit in many cases. Although in some cases, the causes of central inflammatory responses are clear--for example those due to viral infection in AIDS dementia, or those due to the secretion of proinflammatory substances by activated lymphocytes in multiple sclerosis--in other conditions the factors that allow the initiation of brain inflammation are not well understood; nor is it well known why brain inflammatory activation is not as well restricted as it is in the periphery. The concept is emerging that perturbation of endogenous regulatory mechanisms could be an important factor for initiation, maintenance, and lack of resolution of brain inflammation. Conversely, activation of intrinsic regulatory neuronal pathways could provide protection in neuroinflammatory conditions. This concept is the extension of the principle of "central neurogenic neuroprotection" formulated by Donald Reis and colleagues, which contends the existence of neuronal circuits that protect the brain against the damage initiated by excitotoxic injury. In this paper we will review work initiated in the Reis laboratory establishing that activation of endogenous neural circuits can exert anti-inflammatory actions in brain, present data suggesting that these effects could be mediated by noradrenaline, and summarize recent studies suggesting that loss of noradrenergic locus ceruleus neurons contributes to inflammatory activation in Alzheimer's disease.},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/14514020}{14514020}] }
}
@article{pmid12887689,
  author = {Klotz, L.  and Sastre, M.  and Kreutz, A.  and Gavrilyuk, V.  and Klockgether, T.  and Feinstein, D. L.  and Heneka, M. T. },
  title = {{N}oradrenaline induces expression of peroxisome proliferator activated receptor gamma ({P}{P}{A}{R}gamma) in murine primary astrocytes and neurons},
  journal = {J. Neurochem.},
  year = {2003},
  volume = {86},
  number = {4},
  pages = {907--916},
  month = {Aug},
  abstract = {Cerebral inflammatory events play an important part in the pathogenesis of Alzheimer's disease (AD). Agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear hormone receptor that mediates anti-inflammatory actions of non-steroidal anti-inflammatory drugs (NSAIDs) and thiazolidinediones, have been therefore proposed as a potential treatment of AD. Experimental evidence suggests that cortical noradrenaline (NA) depletion due to degeneration of the locus ceruleus (LC) - a pathological hallmark of AD - plays a permissive role in the development of inflammation in AD. To study a possible relationship between NA depletion and PPARgamma-mediated suppression of inflammation we investigated the influence of NA on PPARgamma expression in murine primary cortical astrocytes and neurons. Incubation of astrocytes and neurons with 100 micro m NA resulted in an increase of PPARgamma mRNA as well as PPARgamma protein levels in both cell types. These effects were blocked by the beta-adrenergic antagonist propranolol but not by the alpha-adrenergic antagonist phentolamine, suggesting that they might be mediated by beta-adrenergic receptors. Our results indicate for the first time that PPARgamma expression can be modulated by the cAMP signalling pathway, and suggest that the anti-inflammatory effects of NA on brain cells may be partly mediated by increasing PPARgamma levels. Conversely, decreased NA due to LC cell death in AD may reduce endogenous PPARgamma expression and therefore potentiate neuroinflammatory processes.},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/12887689}{12887689}] }
}
@article{pmid12744773,
  author = {Harzheim, M.  and Altenschmidt, M.  and Heneka, M. T.  and Schroder, R.  and Klockgether, T.  and Schmidt, S. },
  title = {{I}{F}{N}-beta1a ({R}ebif) modifies the expression of microfilament-associated cell-cell contacts in {C}6 glioma cells},
  journal = {J. Interferon Cytokine Res.},
  year = {2003},
  volume = {23},
  number = {2},
  pages = {83--89},
  month = {Feb},
  abstract = {Multiple sclerosis (MS) is a chronic inflammatory disease characterized by multifocal demyelination and axonal damage in the central nervous system (CNS). The disruption of the endothelial blood-brain barrier (BBB) with consecutive transmigration of inflammatory cells into the brain parenchyma is of critical importance in the pathogenesis of MS. The integrity of the BBB and the adjacent network of glial cells partially depends on the assembly of intercellular contacts between astrocytes. We demonstrate that recombinant interferon-gamma (rIFN-gamma), a proinflammatory cytokine critically involved in the disruption of the BBB, downregulates the expression of the cell adhesion molecules N-cadherin and vinculin in astrocytic C6 cells using Western blot and immunofluorescence microscopy. By contrast, IFN-beta1a, an established treatment for relapsing-remitting MS, increases the expression of N-cadherin and vinculin and partly inhibits the downregulation of these adhesion molecules by phytohemagglutinin (PHA)-stimulated IFN-gamma-secreting human T lymphocytes in coculture experiments. In summary, we demonstrate that IFN-beta1a modifies the assembly of N-cadherin- and vinculin-mediated intercellular contacts between astrocytic C6 cells in vitro. This effect may also contribute to the therapeutic action of IFN-beta1a in MS.},
  note = {[DOI:\href{http://dx.doi.org/10.1089/107999003321455471}{10.1089/107999003321455471}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/12744773}{12744773}] }
}
@article{pmid12675915,
  author = {Heneka, M. T.  and Gavrilyuk, V.  and Landreth, G. E.  and O'Banion, M. K.  and Weinberg, G.  and Feinstein, D. L. },
  title = {{N}oradrenergic depletion increases inflammatory responses in brain: effects on {I}kappa{B} and {H}{S}{P}70 expression},
  journal = {J. Neurochem.},
  year = {2003},
  volume = {85},
  number = {2},
  pages = {387--398},
  month = {Apr},
  abstract = {The inflammatory responses in many cell types are reduced by noradrenaline (NA) binding to beta-adrenergic receptors. We previously demonstrated that cortical inflammatory responses to aggregated amyloid beta (Abeta) are increased if NA levels were first depleted by lesioning locus ceruleus (LC) noradrenergic neurons, which replicates the loss of LC occurring in Alzheimer's disease. To examine the molecular basis for increased responses, we used the selective neurotoxin DSP4 to lesion the LC, and then examined levels of putative anti-inflammatory molecules. Inflammatory responses were achieved by injection of aggregated Abeta1-42 peptide and IL-1beta into frontal cortex, which induced neuronal inducible nitric oxide synthase (iNOS) and microglial IL-1beta expression. DSP4-treatment reduced basal levels of nuclear factor kappa B (NF-kappaB) inhibitory IkappaB proteins, and of heat shock protein (HSP)70. Inflammatory responses were prevented by co-injection (ibuprofen or ciglitzaone) or oral administration (pioglitazone) of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. Treatment with PPARgamma agonists restored IkappaBalpha, IkappaBbeta, and HSP70 levels to values equal or above those observed in control animals, and reduced activation of cortical NF-kappaB. These results suggest that noradrenergic depletion reduces levels of anti-inflammatory molecules which normally limit cortical responses to Abeta, and that PPARgamma agonists can reverse that effect. These findings suggest one mechanism by which PPARgamma agonists could provide benefit in neurological diseases having an inflammatory component.},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/12675915}{12675915}] }
}
@article{pmid12176079,
  author = {Feinstein, D. L.  and Heneka, M. T.  and Gavrilyuk, V.  and Dello Russo, C.  and Weinberg, G.  and Galea, E. },
  title = {{N}oradrenergic regulation of inflammatory gene expression in brain},
  journal = {Neurochem. Int.},
  year = {2002},
  volume = {41},
  number = {5},
  pages = {357--365},
  month = {Nov},
  abstract = {It is now well accepted that inflammatory events contribute to the pathogenesis of numerous neurological disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease, and AID's dementia. Whereas inflammation in the periphery is subject to rapid down regulation by increases in anti-inflammatory molecules and the presence of scavenging soluble cytokine receptors, the presence of an intact blood-brain barrier may limit a similar autoregulation from occurring in brain. Mechanisms intrinsic to the brain may provide additional immunomodulatory functions, and whose dysregulation could contribute to increased inflammation in disease. The findings that noradrenaline (NA) reduces cytokine expression in microglial, astroglial, and brain endothelial cells in vitro, and that modification of the noradrenergic signaling system occurs in some brain diseases having an inflammatory component, suggests that NA could act as an endogenous immunomodulator in brain. Furthermore, accumulating studies indicate that modification of the noradrenergic signaling system occurs in some neurodiseases. In this article, we will briefly review the evidence that NA can modulate inflammatory gene expression in vitro, summarize data supporting a similar immunomodulatory role in brain, and present recent data implicating a role for NA in attenuating the cortical inflammatory response to beta amyloid protein.},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/12176079}{12176079}] }
}
@article{pmid12153485,
  author = {Breidert, T.  and Callebert, J.  and Heneka, M. T.  and Landreth, G.  and Launay, J. M.  and Hirsch, E. C. },
  title = {{P}rotective action of the peroxisome proliferator-activated receptor-gamma agonist pioglitazone in a mouse model of {P}arkinson's disease},
  journal = {J. Neurochem.},
  year = {2002},
  volume = {82},
  number = {3},
  pages = {615--624},
  month = {Aug},
  abstract = {We examined the effect of pioglitazone, a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist of the thiazolidinedione class, on dopaminergic nerve cell death and glial activation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. The acute intoxication of C57BL/6 mice with MPTP led to nigrostriatal injury, as determined by tyrosine hydroxylase (TH) immunocytochemistry, and HPLC detection of striatal dopamine and metabolites. Damage to the nigrostriatal dopamine system was accompanied by a transient activation of microglia, as determined by macrophage antigen-1 (Mac-1) and inducible nitric oxide synthase (iNOS) immunoreactivity, and a prolonged astrocytic response. Orally administered pioglitazone (approximately 20 mg/kg/day) attenuated the MPTP-induced glial activation and prevented the dopaminergic cell loss in the substantia nigra pars compacta (SNpc). In contrast, there was little reduction of MPTP-induced dopamine depletion, with no detectable effect on loss of TH immunoreactivity and glial response in the striatum of pioglitazone-treated animals. Low levels of PPARgamma expression were detected in the ventral mesencephalon and striatum, and were unaffected by MPTP or pioglitazone treatment. Since pioglitazone affects primarily the SNpc in our model, different PPARgamma-independent mechanisms may regulate glial activation in the dopaminergic terminals compared with the dopaminergic cell bodies after acute MPTP intoxication.},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/12153485}{12153485}] }
}
@article{pmid12127152,
  author = {Baltrons, M. A.  and Pedraza, C. E.  and Heneka, M. T.  and Garcia, A. },
  title = {{B}eta-amyloid peptides decrease soluble guanylyl cyclase expression in astroglial cells},
  journal = {Neurobiol. Dis.},
  year = {2002},
  volume = {10},
  number = {2},
  pages = {139--149},
  month = {Jul},
  abstract = {In astroglial cells beta-amyloid peptides (betaA) induce a reactive phenotype and increase expression of NO synthase. Here we show that treatment of rat brain astrocytes with betaA decreases their capacity to accumulate cyclic GMP (cGMP) in response to NO as a result of a decreased expression of soluble guanylyl cyclase (sGC) at the protein and mRNA levels. Potentiation of betaA-induced NO formation by interferon-gamma did not result in a larger decrease in cGMP formation and inhibition of NO synthase failed to reverse down-regulation of sGC, indicating that NO is not involved. The betaA effect was prevented by the protein synthesis inhibitor cycloheximide. Intracerebral betaA injection also decreased sGC beta1 subunit mRNA levels in adult rat hippocampus and cerebellum. A loss of sGC in reactive astrocytes surrounding beta-amyloid plaques could be a mechanism to prevent excess signalling via cGMP at sites of high NO production.},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/12127152}{12127152}] }
}
@article{pmid12112074,
  author = {Feinstein, D. L.  and Galea, E.  and Gavrilyuk, V.  and Brosnan, C. F.  and Whitacre, C. C.  and Dumitrescu-Ozimek, L.  and Landreth, G. E.  and Pershadsingh, H. A.  and Weinberg, G.  and Heneka, M. T. },
  title = {{P}eroxisome proliferator-activated receptor-gamma agonists prevent experimental autoimmune encephalomyelitis},
  journal = {Ann. Neurol.},
  year = {2002},
  volume = {51},
  number = {6},
  pages = {694--702},
  month = {Jun},
  abstract = {The development of clinical symptoms in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) involves T-cell activation and migration into the central nervous system, production of glial-derived inflammatory molecules, and demyelination and axonal damage. Ligands of the peroxisome proliferator-activated receptor (PPAR) exert anti-inflammatory effects on glial cells, reduce proliferation and activation of T cells, and induce myelin gene expression. We demonstrate in two models of EAE that orally administered PPARgamma ligand pioglitazone reduced the incidence and severity of monophasic, chronic disease in C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein peptide and of relapsing disease in B10.Pl mice immunized with myelin basic protein. Pioglitazone also reduced clinical signs when it was provided after disease onset. Clinical symptoms were reduced by two other PPARgamma agonists, suggesting a role for PPARgamma activation in protective effects. The suppression of clinical signs was paralleled by decreased lymphocyte infiltration, lessened demyelination, reduced chemokine and cytokine expression, and increased inhibitor of kappa B (IkB) expression in the brain. Pioglitazone also reduced the antigen-dependent interferon-gamma production from EAE-derived T cells. These results suggest that orally administered PPARgamma agonists could provide therapeutic benefit in demyelinating disease.},
  note = {[DOI:\href{http://dx.doi.org/10.1002/ana.10206}{10.1002/ana.10206}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/12112074}{12112074}] }
}
@article{pmid12065618,
  author = {Zander, T.  and Kraus, J. A.  and Grommes, C.  and Schlegel, U.  and Feinstein, D.  and Klockgether, T.  and Landreth, G.  and Koenigsknecht, J.  and Heneka, M. T. },
  title = {{I}nduction of apoptosis in human and rat glioma by agonists of the nuclear receptor {P}{P}{A}{R}gamma},
  journal = {J. Neurochem.},
  year = {2002},
  volume = {81},
  number = {5},
  pages = {1052--1060},
  month = {Jun},
  abstract = {Malignant astrocytomas are among the most common brain tumours and few therapeutic options exist. It has recently been recognized that the ligand-activated nuclear receptor PPARgamma can regulate cellular proliferation and induce apoptosis in different malignant cells. We report the effect of three structurally different PPARgamma agonists inducing apoptosis in human (U87MG and A172) and rat (C6) glioma cells. The PPARgamma agonists ciglitazone, LY171 833 and prostaglandin-J2, but not the PPARalpha agonist WY14643, inhibited proliferation and induced cell death. PPARgamma agonist-induced cell death was characterized by DNA fragmentation and nuclear condensation, as well as inhibited by the synthetic receptor-antagonist bisphenol A diglycidyl ether (BADGE). In contrast, primary murine astrocytes were not affected by PPARgamma agonist treatment. The apoptotic death in the glioma cell lines treated with PPARgamma agonists was correlated with the transient up-regulation of Bax and Bad protein levels. Furthermore, inhibition of Bax expression by specific antisense oligonucleotides protected glioma cells against PPARgamma-mediated apoptosis, indicating an essential role of Bax in PPARgamma-induced apoptosis. However, PPARgamma agonists not only induced apoptosis but also caused redifferentiation as indicated by outgrowth of long processes and expression of the redifferentiation marker N-cadherin in response to PPARgamma agonists. Taken together, treatment of glioma cells with PPARgamma agonists may hold therapeutic potential for the treatment of gliomas.},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/12065618}{12065618}] }
}
@article{pmid12050158,
  author = {Gavrilyuk, V.  and Dello Russo, C.  and Heneka, M. T.  and Pelligrino, D.  and Weinberg, G.  and Feinstein, D. L. },
  title = {{N}orepinephrine increases {I} kappa {B} alpha expression in astrocytes},
  journal = {J. Biol. Chem.},
  year = {2002},
  volume = {277},
  number = {33},
  pages = {29662--29668},
  month = {Aug},
  abstract = {The neurotransmitter norepinephrine (NE) can inhibit inflammatory gene expression in glial cells; however, the mechanisms involved are not clear. In primary astrocytes, NE dose-dependently increased the expression of inhibitory I kappa B alpha protein accompanied by an increase in steady state levels of I kappa B alpha mRNA. Maximal increases were observed at 30-60 min for the mRNA and at 4 h for protein, and these effects were mediated by NE binding to beta-adrenergic receptors. NE activated a 1.3-kilobase I kappa B alpha promoter transfected into astrocytes or C6 glioma cells, and this activation was prevented by a beta-antagonist and by protein kinase A inhibitors but not by an NF kappa B inhibitor. NE increased I kappa B alpha protein in both the cytosolic and the nuclear fractions, suggesting an increase in nuclear uptake of I kappa B alpha. I kappa B alpha was detected in the frontal cortex of normal adult rats, and its levels were reduced if central NE levels were depleted by lesion of the locus ceruleus. The reduction of brain I kappa B alpha levels was paralleled by increased inflammatory responses to lipopolysaccharide. These results demonstrate that I kappa B alpha expression is regulated by NE at both transcriptional and post-transcriptional levels, which could contribute to the observed anti-inflammatory properties of NE in vitro and in vivo.},
  note = {[DOI:\href{http://dx.doi.org/10.1074/jbc.M203256200}{10.1074/jbc.M203256200}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/12050158}{12050158}] }
}
@article{pmid11923407,
  author = {Heneka, M. T.  and Galea, E.  and Gavriluyk, V.  and Dumitrescu-Ozimek, L.  and Daeschner, J.  and O'Banion, M. K.  and Weinberg, G.  and Klockgether, T.  and Feinstein, D. L. },
  title = {{N}oradrenergic depletion potentiates beta -amyloid-induced cortical inflammation: implications for {A}lzheimer's disease},
  journal = {J. Neurosci.},
  year = {2002},
  volume = {22},
  number = {7},
  pages = {2434--2442},
  month = {Apr},
  abstract = {Degeneration of locus ceruleus (LC) neurons and reduced levels of norepinephrine (NE) in LC projection areas are well known features of Alzheimer's disease (AD); however, the consequences of those losses are not clear. Because inflammatory mediators contribute to AD pathogenesis and because NE can suppress inflammatory gene expression, we tested whether LC loss influenced the brain inflammatory gene expression elicited by amyloid beta (Abeta). Adult rats were injected with the selective neurotoxin N-(2-chloroethyl)-N-ethyl-2 bromobenzylamine (DSP4) to induce LC death and subsequently injected in the cortex with Abeta (aggregated 1-42 peptide). DSP4 treatment potentiated the Abeta-dependent induction of inflammatory nitric oxide synthase (iNOS), interleukin (IL)-1beta, and IL-6 expression compared with control animals. In contrast, the induction of cyclooxygenase-2 expression was not modified by DSP4 treatment. In control animals, injection of Abeta induced iNOS primarily in microglial cells, whereas in DSP4-treated animals, iNOS was localized to neurons, as is observed in AD brains. Injection of Abeta increased IL-1beta expression initially in microglia and at later times in astrocytes, and expression levels were greater in DSP4-treated animals than in controls. The potentiating effects of DSP4 treatment on iNOS and IL-1beta expression were attenuated by coinjection with NE or the beta-adrenergic receptor agonist isoproterenol. These data demonstrate that LC loss and NE depletion augment inflammatory responses to Abeta and suggest that LC loss in AD is permissive for increased inflammation and neuronal cell death.},
  note = {[DOI:\href{http://dx.doi.org/20026222}{20026222}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/11923407}{11923407}] }
}
@article{pmid11835313,
  author = {Murphy, P.  and Sharp, A.  and Shin, J.  and Gavrilyuk, V.  and Dello Russo, C.  and Weinberg, G.  and Sharp, F. R.  and Lu, A.  and Heneka, M. T.  and Feinstein, D. L. },
  title = {{S}uppressive effects of ansamycins on inducible nitric oxide synthase expression and the development of experimental autoimmune encephalomyelitis},
  journal = {J. Neurosci. Res.},
  year = {2002},
  volume = {67},
  number = {4},
  pages = {461--470},
  month = {Feb},
  abstract = {The production of nitric oxide by the inflammatory isoform of nitric oxide synthase (NOS2) in brain glial cells is thought to contribute to the causes and development of neurological diseases and trauma. We previously demonstrated that activation of a heat shock response (HSR) by hyperthermia reduced NOS2 expression in vitro, and in vivo attenuated the clinical and histological symptoms of the demyelinating disease experimental autoimmune encephalomyelitis (EAE; Heneka et al. [2001] J. Neurochem. 77:568-579). Benzoquinoid ansamycins are fungal-derived antibiotics with tyrosine kinase inhibitory properties, and which also induce a HSR by allowing activation of HS transcription factor HSF1. We now show that two members of this class of drugs (geldanamycin and 17-allylamino-17-demethoxygeldanamycin) also induce a HSR in primary rat astrocytes and rat C6 glioma cells. Both drugs dose-dependently reduced nitrite accumulation, NOS2 steady-state mRNA levels, and the cytokine-dependent activation of a rat 2.2-kB NOS2 promoter construct stably expressed in C6 cells. These inhibitory effects were partially reversed by quercetin, a bioflavonoid which prevents HSF1 binding to DNA and thus attenuates the HSR. Ansamycins increased mRNA levels of the inhibitory IkappaBalpha protein, suggesting that inhibition of NFkappaB activation could contribute to their suppressive effects. Finally, in C57BL/6 mice actively immunized to develop EAE, a single injection of geldanamycin at 3 days after immunization reduced disease onset by over 50\%. These results indicate that ansamycins can exert potent anti-inflammatory effects on brain glial cells which may provide therapeutic benefit in neuroinflammatory diseases.},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/11835313}{11835313}] }
}
@article{pmid11755002,
  author = {Landreth, G. E.  and Heneka, M. T. },
  title = {{A}nti-inflammatory actions of peroxisome proliferator-activated receptor gamma agonists in {A}lzheimer's disease},
  journal = {Neurobiol. Aging},
  year = {2001},
  volume = {22},
  number = {6},
  pages = {937--944},
  abstract = {The role of inflammatory processes in the brains of Alzheimer's Disease (AD) patients has recently attracted considerable interest. Indeed, the only demonstrated effective therapy for AD patients is long-term treatment with non-steroidal anti-inflammatory drugs (NSAIDs). The mechanistic basis of the efficacy of NSAIDs in AD remains unclear. However, the recent recognition that NSAIDs can bind to and activate the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma), has offered an explanation for the action of these drugs in AD. PPARgamma activation leads to the inhibition of microglial activation and the expression of a broad range of proinflammatory molecules. The newly appreciated anti-inflammatory actions of PPARgamma agonists may allow novel therapies for AD and other CNS indications with an inflammatory component.},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/11755002}{11755002}] }
}
@article{pmid11556547,
  author = {Heneka, M. T.  and Wiesinger, H.  and Dumitrescu-Ozimek, L.  and Riederer, P.  and Feinstein, D. L.  and Klockgether, T. },
  title = {{N}euronal and glial coexpression of argininosuccinate synthetase and inducible nitric oxide synthase in {A}lzheimer disease},
  journal = {J. Neuropathol. Exp. Neurol.},
  year = {2001},
  volume = {60},
  number = {9},
  pages = {906--916},
  month = {Sep},
  abstract = {The enzyme argininosuccinate synthetase (ASS) is the rate limiting enzyme in the metabolic pathway leading from L-citrulline to L-arginine, the physiological substrate of all isoforms of nitric oxide synthases (NOS). ASS and inducible NOS (iNOS) expression in neurons and glia was investigated by immunohistochemistry in brains of Alzheimer disease (AD) patients and nondemented, age-matched controls. In 3 areas examined (hippocampus, frontal, and entorhinal cortex), a marked increase in neuronal ASS and iNOS expression was observed in AD brains. GFAP-positive astrocytes expressing ASS were not increased in AD brains versus controls, whereas the number of iNOS expressing GFAP-positive astrocytes was significantly higher in AD brains. Density measurements revealed that ASS expression levels were significantly higher in glial cells of AD brains. Colocalization of ASS and iNOS immunoreactivity was detectable in neurons and glia. Occasionally, both ASS-and iNOS expression was detectable in CD 68-positive activated microglia cells in close proximity to senile plaques. These results suggest that neurons and astrocytes express ASS in human brain constitutively, whereas neuronal and glial ASS expression increases parallel to iNOS expression in AD. Because an adequate supply of L-arginine is indispensable for prolonged NO generation, coinduction of ASS enables cells to sustain NO generation during AD by replenishing necessary supply of L-arginine.},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/11556547}{11556547}] }
}
@article{pmid11299319,
  author = {Heneka, M. T.  and Sharp, A.  and Murphy, P.  and Lyons, J. A.  and Dumitrescu, L.  and Feinstein, D. L. },
  title = {{T}he heat shock response reduces myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in mice},
  journal = {J. Neurochem.},
  year = {2001},
  volume = {77},
  number = {2},
  pages = {568--579},
  month = {Apr},
  abstract = {The stress response (SR) can block inflammatory gene expression by preventing activation of transcription factor nuclear factor-kappa B (NF-kappaB). As inflammatory gene expression contributes to the pathogenesis of demyelinating diseases, we tested the effects of the SR on the progression of the demyelinating disease experimental autoimmune encephalomyelitis (EAE). EAE was actively induced in C57BL/6 mice using an encephalitogenic myelin oligodendrocyte glycoprotein (MOG(35-55)) peptide. Whole body hyperthermia was used to induce a heat shock response (HSR) in immunized mice 2 days after the booster MOG(35-55) peptide injection. The HSR reduced the incidence of EAE by 70\%, delayed disease onset by 6 days, and attenuated disease severity. The HSR attenuated leukocyte infiltration into CNS assessed by quantitation of perivascular infiltrates, and by reduced staining for CD4 and CD25 immunopositive T-cells. T-cell activation, assessed by the production of interferon gamma (IFNgamma) in response to MOG(35-55), was also decreased by the HSR. The HSR reduced inflammatory gene expression in the brain that normally occurs during EAE, including the early increase in RANTES (regulated on activation of normal T-cell expressed and secreted) expression, and the later expression of the inducible form of nitric oxide synthase. The early activation of transcription factor NF-kappaB was also blocked by the HSR. The finding that the SR reduces inflammation in the brain and the clinical severity of EAE opens a novel therapeutic approach for prevention of autoimmune diseases.},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/11299319}{11299319}] }
}
@article{pmid11240010,
  author = {Heneka, M. T.  and Feinstein, D. L. },
  title = {{E}xpression and function of inducible nitric oxide synthase in neurons},
  journal = {J. Neuroimmunol.},
  year = {2001},
  volume = {114},
  number = {1-2},
  pages = {8--18},
  month = {Mar},
  abstract = {Enzymatically derived nitric oxide (NO) has been implicated in numerous physiological and pathological processes in the brain. Whereas during development NO participates in developmental and maturation processes, excess NO production in the adult in response to inflammation, injury, or trauma participates in both cell death and repair. The expression and activity of the inducible isoform of NO synthase (iNOS) play a pivotal role in sustained and elevated NO release. Recent evidence suggests that neurons can respond to proinflammatory stimuli and take part in brain inflammation. Neuronal iNOS expression has been described in different experimental settings, including cytokine stimulation of neuronal cell lines and primary neurons in vitro as well as in animal models of stroke and neurodegeneration. This article outlines different conditions leading to iNOS gene transcription and expression in neurons and neuronal cells and highlights the potential impact on human brain inflammation and neurodegeneration.},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/11240010}{11240010}] }
}
@article{pmid11220752,
  author = {Heneka, M. T.  and Landreth, G. E.  and Feinstein, D. L. },
  title = {{R}ole for peroxisome proliferator-activated receptor-gamma in {A}lzheimer's disease},
  journal = {Ann. Neurol.},
  year = {2001},
  volume = {49},
  number = {2},
  pages = {276},
  month = {Feb},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/11220752}{11220752}] }
}
@article{pmid11152291,
  author = {Hoffmann, J.  and Twiesselmann, C.  and Kummer, M. P.  and Romagnoli, P.  and Herzog, V. },
  title = {{A} possible role for the {A}lzheimer amyloid precursor protein in the regulation of epidermal basal cell proliferation},
  journal = {Eur. J. Cell Biol.},
  year = {2000},
  volume = {79},
  number = {12},
  pages = {905--914},
  month = {Dec},
  abstract = {The regulation of epidermal growth involves a number of ions, growth factors and cytokines and possibly additional but as yet unknown factors. Here we report on the potential role of the secretory N-terminal domain (sAPP) of the Alzheimer amyloid precursor protein (APP) in the regulation of keratinocyte proliferation. In human skin APP was detectable predominantly in the basal cell layer of the epidermis whereas the immunocytochemical signal in the underlying mesenchymal tissue was very low. Cultured normal human keratinocytes expressed the three APP isoforms 695, 751 and 770 with highest values for the isoforms 751 and 770. HaCaT cells, a spontaneously immortalized human keratinocyte cell line, exhibited almost identical patterns in the expression of the APP isoforms and in the release of endogenous sAPP. In HaCaT cells, recombinant sAPP (sAPPrec) was found to compete with endogenous sAPP for the same binding sites. Binding of sAPPrec was specific and occurred in microdomains of approximately 0.1 to approximately 0.3 microm in diameter. At 10 nM, sAPPrec binding induced a 2- to 4-fold increase in the rate of cell growth. sAPP concentrations in the conditioned media were found to reach 5-20 nM which is in the mitogenic range of sAPPrec. The proliferative effect of sAPP was inhibited by approximately 50\% when antisense oligonucleotides directed against the APP mRNA were applied. The predominant expression of},
  note = {[DOI:\href{http://dx.doi.org/10.1078/0171-9335-00117}{10.1078/0171-9335-00117}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/11152291}{11152291}] }
}
@article{pmid11086167,
  author = {Hitzel, C.  and Kanzler, H.  and Konig, A.  and Kummer, M. P.  and Brix, K.  and Herzog, V.  and Koch, N. },
  title = {{T}hyroglobulin type-{I}-like domains in invariant chain fusion proteins mediate resistance to cathepsin {L} digestion},
  journal = {FEBS Lett.},
  year = {2000},
  volume = {485},
  number = {1},
  pages = {67--70},
  month = {Nov},
  abstract = {The MHCII associated invariant chain isoform Ii41 shows homology to a repeat in thyroglobulin (TgR). We show that the Ii31 isoform, which lacks the TgR-like domain, is sensitive to cathepsin L treatment whereas Ii41 displays substantial resistance. The TgR-like sequence of Ii41 was exchanged for thyroglobulin type-IA and -IB repeats, that contain six or four cysteine residues. Resistance to cathepsin L digestion was maintained upon substitution of the Ii41 TgR for homologous sequences from TgR type-IA. Mutation of a conserved cysteine in the TgR domain of an Ii fusion protein strongly reduced resistance to cathepsin L digestion.},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/11086167}{11086167}] }
}
@article{pmid10995830,
  author = {Heneka, M. T.  and Klockgether, T.  and Feinstein, D. L. },
  title = {{P}eroxisome proliferator-activated receptor-gamma ligands reduce neuronal inducible nitric oxide synthase expression and cell death in vivo},
  journal = {J. Neurosci.},
  year = {2000},
  volume = {20},
  number = {18},
  pages = {6862--6867},
  month = {Sep},
  abstract = {Expression of the inducible form of nitric oxide synthase (iNOS) in brain may contribute to neurotoxicity in Alzheimer's disease (AD). Expression of iNOS can be induced in cerebellar granule cells (CGCs) in vivo as well as in vitro, allowing these cells to be used to study regulation of neuronal iNOS expression. We report here that microinjection of bacterial lipopolysaccharide and interferon gamma into rat cerebellum induced iNOS expression in CGCs and subsequent cell death assessed by staining for DNA fragmentation. Co-injection of three structurally distinct agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma), including the antidiabetic thiazolidinedione troglitazone, the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen, and the prostanoid 15-deoxy-Delta(12,14) prostaglandin J(2), reduced both iNOS expression and cell death, whereas co-injection of the selective cyclo-oxygenase inhibitor NS-398 had no effect. These data demonstrate that PPARgamma agonists can modulate inflammatory responses in brain. Because sustained medication with NSAIDs reduces the risk and delays the onset of AD, these results further suggest that NSAIDs provide therapeutic value by binding to PPARgamma present in AD brain, thereby preventing iNOS expression and neuronal cell death.},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/10995830}{10995830}] }
}
@article{pmid10826530,
  author = {Heneka, M. T.  and Sharp, A.  and Klockgether, T.  and Gavrilyuk, V.  and Feinstein, D. L. },
  title = {{T}he heat shock response inhibits {N}{F}-kappa{B} activation, nitric oxide synthase type 2 expression, and macrophage/microglial activation in brain},
  journal = {J. Cereb. Blood Flow Metab.},
  year = {2000},
  volume = {20},
  number = {5},
  pages = {800--811},
  month = {May},
  abstract = {The heat shock response (HSR) provides protection against stress-induced damage, and also prevents initiation of inflammatory gene expression via inhibition of NFkappaB activation. This article describes experiments demonstrating that the HSR prevents induction of nitric oxide synthase type 2 (NOS2) in rat brain. Twenty four hours after intrastriatal injection of lipopolysaccharide (LPS), IL-1beta, and IFN-gamma, NOS2 immunoreactive cells were detected in striatum, corpus callosum, and to a lesser extent in cortex. Induction of a HSR by whole body warming to 41 degrees C for 20 minutes, done 1 day before LPS plus cytokine injection, reduced the number of NOS2-positive staining cells to background levels. Staining for EDI antigen revealed that the HSR also suppressed microglial/brain macrophage activation in the same areas. Striatal injection of LPS and cytokines induced the rapid activation of NFkappaB, and this activation was prevented by prior HS, which also increased brain IkappaB-alpha expression. These results suggest that establishment of a HSR can reduce inflammatory gene expression in brain, mediated by inhibition of NFkappaB activation, and may therefore offer a novel approach to treatment and prevention of neurological disease and trauma.},
  note = {[DOI:\href{http://dx.doi.org/10.1097/00004647-200005000-00006}{10.1097/00004647-200005000-00006}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/10826530}{10826530}] }
}
@article{pmid10781735,
  author = {Heneka, M. T.  and Dumitrescu, L.  and Loschmann, P. A.  and Wullner, U.  and Klockgether, T. },
  title = {{T}emporal, regional, and cell-specific changes of i{N}{O}{S} expression after intrastriatal microinjection of interferon gamma and bacterial lipopolysaccharide},
  journal = {J. Chem. Neuroanat.},
  year = {2000},
  volume = {18},
  number = {4},
  pages = {167--179},
  month = {Apr},
  abstract = {Here we study expression of the inducible isoform of nitric oxide synthases after intrastriatal microinjection of interferon-gamma and bacterial lipopolysaccharide in the rat at different time points to detect time- and localisation-dependent changes of iNOS expression. Three different areas in the striatum and the corpus callosum were evaluated. Antibodies against the glial fibrillary acidic protein and the microglia/brain macrophage epitope ED1 were used to detect colocalization of inducible nitric oxide synthase with astrocytes or activated microglia/brain macrophages, respectively. Inducible nitric oxide synthase-positive cells occurred first in intravascular and perivascular cells at 4 h. Perivascular and parenchymal inducible nitric oxide synthase expression increased up to 24 h in the striatum, whereas in the corpus callosum inducible nitric oxide synthase expression was maximal after 16 h. Inducible nitric oxide synthase was still present in perivascular cells 7 days after immunostimulation. At all time points, inducible nitric oxide synthase was predominantly detected in ED1-positive microglia/brain. Nitrotyrosine immunohistochemistry was performed to detect NO-mediated nitration of proteins at all time points. Nitrotyrosine-positive neurons and microglial cells were detected from 24 h until 7 days after immunostimulation and were absent in controls. Detailed knowledge of the changes in the time course and cellular source of inducible nitric oxide synthase expression following brain immunostimulation provide a basis for establishing treatment strategies and windows of therapeutic intervention during neuroinflammation.},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/10781735}{10781735}] }
}
@article{pmid10695726,
  author = {Heneka, M. T.  and Feinstein, D. L.  and Galea, E.  and Gleichmann, M.  and Wullner, U.  and Klockgether, T. },
  title = {{P}eroxisome proliferator-activated receptor gamma agonists protect cerebellar granule cells from cytokine-induced apoptotic cell death by inhibition of inducible nitric oxide synthase},
  journal = {J. Neuroimmunol.},
  year = {1999},
  volume = {100},
  number = {1-2},
  pages = {156--168},
  month = {Dec},
  abstract = {Cerebellar granule cells (CGCs) can express the inducible isoform of nitric oxide synthase (iNOS) in response to inflammatory stimuli. We demonstrate that induction of iNOS in CGCs by bacterial lipopolysaccharide and pro-inflammatory cytokines results in cell death that was potentiated by excess L-arginine and inhibited by the selective iNOS inhibitor, 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine. The NO-mediated cell death was accompanied by increased caspase-3-like activity, DNA fragmentation and positive terminal transferase dUTP nick end labeling (TUNEL), suggesting that apoptosis mediates CGC cell death. Incubation of CGCs with the non-steroidal anti-inflammatory drugs (NSAIDs), ibuprofen or indomethacin, or with 15-deoxy-delta12,14 prostaglandin J2 (PGJ2) downregulates iNOS expression and reduces subsequent cell death. Since in other cell types, both NSAIDs and PGJ2 can activate the peroxisome proliferator-activated receptor-gamma (PPARgamma) and downregulate cytokine levels and iNOS expression, and since CGCs express PPARgamma in vivo and in vitro, our data suggest that activation of CGC PPARgamma mediates iNOS suppression and reduced cell death. Because PPARgamma is expressed in brains of Alzheimer's Disease (AD) patients, in which neuronal iNOS expression and apoptotic cell death have been described, these results may help explain the basis for the beneficial effects of NSAIDs in AD.},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/10695726}{10695726}] }
}
@article{pmid10458597,
  author = {Heneka, M. T.  and Schmidlin, A.  and Wiesinger, H. },
  title = {{I}nduction of argininosuccinate synthetase in rat brain glial cells after striatal microinjection of immunostimulants},
  journal = {J. Cereb. Blood Flow Metab.},
  year = {1999},
  volume = {19},
  number = {8},
  pages = {898--907},
  month = {Aug},
  abstract = {The enzyme argininosuccinate synthetase (ASS) initiates the metabolic pathway leading from L-citrulline to L-arginine, the only physiological substrate of all isoforms of nitric oxide synthases. The presence of ASS in glial cells in vivo was investigated by immunohistochemical methods in a model of rat brain inflammation. Phosphate-buffered saline or a mixture of bacterial lipopolysaccharide and interferon-gamma was injected into the left striatum, and animals were killed 24 hours later. Ipsilateral and contralateral sides of brain sections were incubated with an antiserum against ASS or antibodies against cell-specific markers. In the three areas examined, striatum, corpus callosum, and cortex, a strong induction of ASS immunoreactivity was observed in glial cells after injection of immunostimulants. A detailed quantitative analysis of double-stained sections revealed that ASS was almost exclusively expressed in reactive, ED1-positive microglial cells/brain macrophages in immunostimulant- or sham-injected ipsilateral sides of the sections. Furthermore, ASS/ED1 costaining was observed in perivascular cells. Colocalization of ASS with astroglial marker glial fibrillary acidic protein was given only occasionally after immunostimulation. ASS-positive neurons were detected in control and experimental animals; staining intensity was comparable in both cases. The results suggest that neurons express ASS constitutively, whereas the enzyme is induced in glial cells in response to proinflammatory stimuli. This finding is the first demonstration of an induction of a pathway auxiliary to generation of nitric oxide in brain in response to immunostimulants and provides new insight into neural arginine metabolism.},
  note = {[DOI:\href{http://dx.doi.org/10.1097/00004647-199908000-00009}{10.1097/00004647-199908000-00009}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/10458597}{10458597}] }
}
@article{pmid10203688,
  author = {Schulz, J. B.  and Weller, M.  and Matthews, R. T.  and Heneka, M. T.  and Groscurth, P.  and Martinou, J. C.  and Lommatzsch, J.  and von Coelln, R.  and Wullner, U.  and Loschmann, P. A.  and Beal, M. F.  and Dichgans, J.  and Klockgether, T. },
  title = {{E}xtended therapeutic window for caspase inhibition and synergy with {M}{K}-801 in the treatment of cerebral histotoxic hypoxia},
  journal = {Cell Death Differ.},
  year = {1998},
  volume = {5},
  number = {10},
  pages = {847--857},
  month = {Oct},
  abstract = {In rats, striatal histotoxic hypoxic lesions produced by the mitochondrial toxin malonate resemble those of focal cerebral ischemia. Intrastriatal injections of malonate induced cleavage of caspase-2 beginning at 6 h, and caspase-3-like activity as identified by DEVD biotin affinity-labeling within 12 h. DEVD affinity-labeling was prevented and lesion volume reduced in transgenic mice overexpressing BCL-2 in neuronal cells. Intrastriatal injection of the tripeptide, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD-fmk), a caspase inhibitor, at 3 h, 6 h, or 9 h after malonate injections reduced the lesion volume produced by malonate. A combination of pretreatment with the NMDA antagonist, dizocilpine (MK-801), and delayed treatment with zVAD-fmk provided synergistic protection compared with either treatment alone and extended the therapeutic window for caspase inhibition to 12 h. Treatment with cycloheximide and zVAD-fmk, but not with MK-801, blocked the malonate-induced cleavage of caspase-2. NMDA injections alone resulted in a weak caspase-2 cleavage. These results suggest that malonate toxicity induces neuronal death by more than one pathway. They strongly implicate early excitotoxicity and delayed caspase activation in neuronal loss after focal ischemic lesions and offer a new strategy for the treatment of stroke.},
  note = {[DOI:\href{http://dx.doi.org/10.1038/sj.cdd.4400420}{10.1038/sj.cdd.4400420}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/10203688}{10203688}] }
}
@article{pmid10026239,
  author = {Hoffmann, J.  and Pietrzik, C. U.  and Kummer, M. P.  and Twiesselmann, C.  and Bauer, C.  and Herzog, V. },
  title = {{B}inding and selective detection of the secretory {N}-terminal domain of the alzheimer amyloid precursor protein on cell surfaces},
  journal = {J. Histochem. Cytochem.},
  year = {1999},
  volume = {47},
  number = {3},
  pages = {373--382},
  month = {Mar},
  abstract = {The secretory N-terminal domain of the Alzheimer amyloid precursor protein (sAPP) evokes specific responses in cells on binding to their surfaces. Because APP is expressed in a large variety of cell types, the localization of sAPP binding requires detection techniques that selectively recognize sAPP as a ligand. For this purpose, we prepared antibodies against recombinant sAPP695 (sAPPrec) previously expressed in E. coli. Such antibodies were found to distinguish between sAPPrec and cellular APP or sAPP, as shown by immunocytochemistry and by immunoblot. In addition, they allowed the selective localization of bound sAPPrec on cell surfaces without any signal from cellular APP or sAPP. Saturation of sAPPrec binding to cell surfaces, as determined radiometrically, was reached at 10 nM [125I]-sAPPrec. Binding was specific because it was almost completely inhibited by a 100-fold excess of unlabeled sAPPrec. This specificity of binding was confirmed by surface plasmon resonance spectroscopy. Binding of sAPPrec to cell surfaces occurred in patches and was dependent on the state of cell differentiation. The sAPPrec used in this study contains heparin binding sites, but enzymatic removal of cell surface associated heparin did not affect sAPPrec binding. Aldehyde fixation of cells strongly inhibited their ability to bind sAPPrec. The data point to a fixation-sensitive sAPPrec binding protein which is detectable in the form of patches and therefore is part of assembled cell surface microdomains.},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/10026239}{10026239}] }
}
@article{pmid9648854,
  author = {Heneka, M. T.  and Loschmann, P. A.  and Gleichmann, M.  and Weller, M.  and Schulz, J. B.  and Wullner, U.  and Klockgether, T. },
  title = {{I}nduction of nitric oxide synthase and nitric oxide-mediated apoptosis in neuronal {P}{C}12 cells after stimulation with tumor necrosis factor-alpha/lipopolysaccharide},
  journal = {J. Neurochem.},
  year = {1998},
  volume = {71},
  number = {1},
  pages = {88--94},
  month = {Jul},
  abstract = {Exposure of neuronal PC12 cells, differentiated by nerve growth factor, to tumor necrosis factor-alpha (TNF-alpha) and bacterial lipopolysaccharide (LPS) resulted in de novo synthesis of inducible nitric oxide synthase (iNOS) mRNA and protein with an increase up to 24 h. Brain NOS expression was unaffected. The induction of iNOS in differentiated PC12 cells was associated with cell death characterized by features of apoptosis. The NOS inhibitors N-monomethylarginine, aminoguanidine, and 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine.HCl prevented TNF-alpha/LPS-induced cell death and DNA fragmentation, suggesting that the TNF-alpha/LPS-induced cell death is mediated by iNOS-derived NO. This hypothesis is supported by the finding that addition of L-arginine, which serves as a precursor and limiting factor of enzyme-derived NO production, potentiated TNF-alpha/LPS-induced loss of viability.},
  note = {[PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/9648854}{9648854}] }
}
@article{pmid9215597,
  author = {Loschmann, P. A.  and Wullner, U.  and Heneka, M. T.  and Schulz, J. B.  and Kunow, M.  and Wachtel, H.  and Klockgether, T. },
  title = {{D}ifferential interaction of competitive {N}{M}{D}{A} and {A}{M}{P}{A} antagonists with selective dopamine {D}-1 and {D}-2 agonists in a rat model of {P}arkinson's disease},
  journal = {Synapse},
  year = {1997},
  volume = {26},
  number = {4},
  pages = {381--391},
  month = {Aug},
  abstract = {Stimulation of the dopamine (DA) D-2 and D-1 receptors results in behavioural activation (i.e., induction of contralateral rotations) in 6-hydroxydopamine (6-OHDA) substantia nigra lesioned rats. Competitive N-methyl-D-aspartate (NMDA) antagonists as well as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) antagonists potentiate the stimulatory responses to threshold doses of L-DOPA or the mixed dopamine D-1/D-2 agonist apomorphine in this model, indicating the potential of such combinations for the management of Parkinson's disease. Neuroanatomic and electrophysiologic data indicate a differential distribution of DA D-1 and DA D-2 receptors within motor loops of the basal ganglia. DA D-1 receptors are preferentially located on GABAergic neurones projecting to the substantia nigra compacta (SNc) and to the substantia nigra reticulata (SNr), whereas DA D-2 receptors are preferentially located on neurones that innervate the external pallidum. NMDA receptors are present in high densities within the striatum, whereas AMPA receptors are enriched in the entopeduncular nucleus/internal pallidum and the SNr. To further characterise the functional interaction between DA and glutamate receptors, we tested the competitive NMDA antagonist 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) and the AMPA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f] quinoxaline (NBQX) following systemic administration in combination with the DA D-2 selective agonist quinpirole or the DAD-1 selective agonist A 68 930 (1R,3S)-1-aminomethyl-5,6-dihydroxy-3-phenylisochroman) in rats with chronic 6-OHDA lesions of the SNc. CPP potentiated quinpirole-induced rotations and did not affect those induced by the D-1 agonist A 68930. By contrast, NBQX had no effect on quinpirole-induced rotations, whereas synergism was seen with A 68930. These results suggest that rotations induced by combined treatment with glutamate antagonists and DA agonists are mediated by different pathways within the basal ganglia, depending on which subtype of receptor is involved. AMPA antagonists could act preferentially by activating the direct motor pathway, whereas NMDA antagonists could modulate the indirect loop.},
  note = {[DOI:\href{http://dx.doi.org/3.0.CO;2-2}{3.0.CO;2-2}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/9215597}{9215597}] }
}
@article{pmid9011575,
  author = {Heneka, M. T.  and Loschmann, P. A.  and Osswald, H. },
  title = {{P}olymerized hemoglobin restores cardiovascular and kidney function in endotoxin-induced shock in the rat},
  journal = {J. Clin. Invest.},
  year = {1997},
  volume = {99},
  number = {1},
  pages = {47--54},
  month = {Jan},
  abstract = {Sepsis and its complications, hypotension, shock, and multiorgan failure continue to represent a significant cause of mortality among hospitalized patients, affecting approximately 200,000 patients per year in the US and 100,000 in Europe (Dal Nogare, A.R. 1991. Am. J. Med. Sci. 302:50-65.). Incidence rates appear to be increasing, probably due to an increase in the population with risk factors such as diabetes or invasive procedures. Activation of cytokines by endotoxins and subsequent formation of nitric oxide is of central pathogeneic importance in sepsis. In this study we show that polymerized bovine hemoglobin (Biopure 2) restores both cardiovascular and renal functions in an endotoxin-induced shock model in rats. These effects are compared to those of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine, and hydroxyethyl starch, the latter currently in clinical use for intravenous volume replacement. Our results clearly indicate that polymerized hemoglobin but not nitric oxide synthase inhibition or volume replacement normalize cardiovascular and kidney function in acute septic shock. This new therapeutic approach is readily applicable to controlled clinical trials because polymerized hemoglobin has been tested in humans and is therefore available for such studies.},
  note = {[PubMed Central:\href{http://www.ncbi.nlm.nih.gov/pmc/articles/PMC507766}{PMC507766}] [DOI:\href{http://dx.doi.org/10.1172/JCI119132}{10.1172/JCI119132}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/9011575}{9011575}] }
}
@article{pmid25832411,
  author = {Heilmann, S.  and Drichel, D.  and Clarimon, J.  and Fernandez, V.  and Lacour, A.  and Wagner, H.  and Thelen, M.  and Hernandez, I.  and Fortea, J.  and Alegret, M.  and Blesa, R.  and Mauleon, A.  and Roca, M. R.  and Kornhuber, J.  and Peters, O.  and Heun, R.  and Frolich, L.  and Hull, M.  and Heneka, M. T.  and Ruther, E.  and Riedel-Heller, S.  and Scherer, M.  and Wiltfang, J.  and Jessen, F.  and Becker, T.  and Tarraga, L.  and Boada, M.  and Maier, W.  and Lleo, A.  and Ruiz, A.  and Nothen, M. M.  and Ramirez, A. },
  title = {{P}{L}{D}3 in non-familial {A}lzheimer's disease},
  journal = {Nature},
  year = {2015},
  volume = {520},
  number = {7545},
  pages = {3--5},
  month = {Apr},
  note = {[DOI:\href{http://dx.doi.org/10.1038/nature14039}{10.1038/nature14039}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/25832411}{25832411}] }
}
@article{pmid25808982,
  author = {Schmidt, R.  and Hofer, E.  and Bouwman, F. H.  and Buerger, K.  and Cordonnier, C.  and Fladby, T.  and Galimberti, D.  and Georges, J.  and Heneka, M. T.  and Hort, J.  and Laczo, J.  and Molinuevo, J. L.  and O'Brien, J. T.  and Religa, D.  and Scheltens, P.  and Schott, J. M.  and Sorbi, S. },
  title = {{E}{F}{N}{S}-{E}{N}{S}/{E}{A}{N} {G}uideline on concomitant use of cholinesterase inhibitors and memantine in moderate to severe {A}lzheimer's disease},
  journal = {Eur. J. Neurol.},
  year = {2015},
  volume = {22},
  number = {6},
  pages = {889--898},
  month = {Jun},
  abstract = {Previous studies have indicated clinical benefits of a combination of cholinesterase inhibitors (ChEI) and memantine over ChEI monotherapy in Alzheimer's disease (AD). Our objective was the development of guidelines on the question of whether combined ChEI/memantine treatment rather than ChEI alone should be used in patients with moderate to severe AD to improve global clinical impression (GCI), cognition, behaviour and activities of daily living (ADL).\\ A systematic review and meta-analysis of randomized controlled trials based on a literature search in ALOIS, the register of the Cochrane Dementia and Cognitive Improvement Group, was carried out with subsequent guideline development according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.\\ Pooled data from four trials including 1549 AD patients in the moderate to severe disease stage demonstrated significant beneficial effects of combination therapy compared to ChEI monotherapy for GCI [standardized mean difference (SMD) -0.20; 95\% confidence interval (CI) -0.31; -0.09], cognitive functioning (SMD -0.27, 95\% CI -0.37; -0.17) and behaviour (SMD -0.19; 95\% CI -0.31; -0.07). The quality of evidence was high for behaviour, moderate for cognitive function and GCI and low for ADL. Agreement of panellists was reached after the second round of the consensus finding procedure. The desirable effects of combined ChEI and memantine treatment were considered to outweigh undesirable effects. The evidence was weak for cognition, GCI and ADL so that the general recommendation for using combination therapy was weak.\\ We suggest the use of a combination of ChEI plus memantine rather than ChEI alone in patients with moderate to severe AD. The strength of this recommendation is weak.},
  note = {[DOI:\href{http://dx.doi.org/10.1111/ene.12707}{10.1111/ene.12707}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/25808982}{25808982}] }
}
@article{pmid25792098,
  author = {Heneka, M. T.  and Carson, M. J.  and Khoury, J. E.  and Landreth, G. E.  and Brosseron, F.  and Feinstein, D. L.  and Jacobs, A. H.  and Wyss-Coray, T.  and Vitorica, J.  and Ransohoff, R. M.  and Herrup, K.  and Frautschy, S. A.  and Finsen, B.  and Brown, G. C.  and Verkhratsky, A.  and Yamanaka, K.  and Koistinaho, J.  and Latz, E.  and Halle, A.  and Petzold, G. C.  and Town, T.  and Morgan, D.  and Shinohara, M. L.  and Perry, V. H.  and Holmes, C.  and Bazan, N. G.  and Brooks, D. J.  and Hunot, S.  and Joseph, B.  and Deigendesch, N.  and Garaschuk, O.  and Boddeke, E.  and Dinarello, C. A.  and Breitner, J. C.  and Cole, G. M.  and Golenbock, D. T.  and Kummer, M. P. },
  title = {{N}euroinflammation in {A}lzheimer's disease},
  journal = {Lancet Neurol},
  year = {2015},
  volume = {14},
  number = {4},
  pages = {388--405},
  month = {Apr},
  abstract = {Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease.},
  note = {[DOI:\href{http://dx.doi.org/10.1016/S1474-4422(15)70016-5}{10.1016/S1474-4422(15)70016-5}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/25792098}{25792098}] }
}
@article{pmid25974006,
  author = {Heneka, M. T.  and Fink, A.  and Doblhammer, G.},
  title = {{E}ffect of pioglitazone medication on the incidence of dementia},
  journal = {Ann. Neurol.},
  year = {2015},
  pages = { },
  month = {May},
  abstract = {PPAR\gamma activating drugs show various salutary effects in preclinical models of neurodegenerative disease. The decade-long clinical usage of these drugs as antidiabetics now allow for evaluation of patient-oriented data sources.\\ Using observational data from 2004-2010, we analyzed the association of pioglitazone and incidence of dementia in a prospective cohort study of 145,928 subjects aged 60 years or above who, at baseline, were free of dementia and insulin-dependent diabetes mellitus. We distinguished between non-diabetics, diabetics without pioglitazone, diabetics with prescriptions of less than eight calendar quarters of pioglitazone and diabetics with eight and more quarters. Cox proportional hazard models explored the relative risk of dementia incidence dependent on pioglitazone use adjusted for sex, age, use of rosiglitazone or metformin and cardiovascular comorbidities.\\ Long-term use of pioglitazone was associated with a lower dementia incidence. Relative to non-diabetics, the cumulative long-term use of pioglitazone reduced the dementia risk by 47\% (RR=0.53, p=0.029). If diabetes patients used pioglitazone less than eight quarters, the dementia risk was comparable to those of non-diabetics (RR=1.16, p=0.317), and diabetes patients without a pioglitazone treatment had a 23\% increase in dementia risk (RR=1.23, p<0.001). We did not find evidence for age effects, nor for selection into pioglitazone treatment due to obesity.\\ These findings indicate that pioglitazone treatment is associated which a reduced dementia risk in initially non-insulin dependent diabetes mellitus patients. Prospective clinical trials are needed to evaluate a possible neuroprotective effect in these patients in an ageing population. This article is protected by copyright. All rights reserved.},
  note = {[DOI:\href{http://dx.doi.org/10.1002/ana.24439}{10.1002/ana.24439}] [PubMed:\href{http://www.ncbi.nlm.nih.gov/pubmed/25974006}{25974006}] }
}

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