Nuclear hormone receptors (NHRs) have been extensively studied for their role on metabolic dysfunction and cardiovascular disease. In particular the peroxisome proliferator–activated receptor γ (PPARγ), the liver X receptors and the retinoid X receptors have been shown to be key for insulin resistance, adipogenesis, athereoscleorsis and vascular inflammation. All these receptors, however, are intimately involved in the regulation of processes involved in neurodegenerative disorders and specific activation of these targets may provide therapeutic benefit (Schütz et al. 2005, Heneka et al. 2005, Heneka et al. 2007).

Experimental evidence suggests that protection from Alzheimer disease by long-term medication with non-steroidal anti-inflammatory drugs is mediated by activation of PPARγ in neurons and microglia by these substances (Sastre et al. 2003, Heneka et al. 2005, Sastre et al. 2006). Likewise, LXRs have been implicated in the modulation of microglial clearance mechanisms guided by astrocyte dependent expression of ABCA1 and modification of the ApoE lipidation status (Terwel et al., 2011). The above described PPARγ and LXR action is, however, synergistically enhanced by retinoid X receptor coactivation. Together this suggests that the above receptors may represent the molecular matrix that links neurodegeneration and systemic metabolic dysfunction. Given the fact that metabolic disturbances and e.g. obesity and high cholesterol intake are critical risk factors for the development of neurodegenerative disease, addressing this link may open new mechanistic insight and further therapeutic avenues.

Current and future work will apply cre-lox based cell and time specific knockout strategies of all the above nuclear hormone receptors in murine models of neurodegenerative disorders and more specifically Alzheimer`s disease and amyotrophic lateral sclerosis. Targeted cells will include neurons, astrocytes and microglial cells. Evaluation will be bidirectional meaning that the consequences of brain cell specific knockouts on metabolism and cardiovascular performance will be studied, while likewise metabolic challenges such as high cholesterol feeding will be analyzed for their effects on neurodegeneration in the absence and presence of the respective nuclear hormone receptor. Analysis of neurodegeneration will include the cognitive assessment as well as in vivo two-photon laser microscopy evaluation of microglial action (Heneka et al. 2010) and neuronal death. APP processing, amyloid beta deposition and synaptosome changes are being analyzed post-mortem in murine Alzheimer disease models while ALS assessment will include motor behaviour analysis, weight, muscular strength as well as motoneuron death, glial inflammation and target organ destruction (Schütz et al. 2005).

Selected Publications:

Heneka MT, Landreth GE, Hull M Drug insight: Peroxisome proliferator-activated receptor γ in CNS disorders (2007) Nat. Rev. Neurol. 3: 496-504.

Heneka MT, Nadrigny F, Regen T, Dumitrescu-Ozimek L, Terwel D, Jardanhazi-Kurutz D, Walter J, Kirchhoff F, Hanisch U, Kummer MP (2010) Locus ceruleus controls Alzheimer disease pathology by modulating microglial functions through norepinephrine. Proc. Natl. Acad. Sci. U.S.A., 107:6058-63.

Heneka MT, Sastre M, Dumitrescu-Ozimek L, Hanke A, Dewachter I, Cuiperi K, O´Banion MK, Klockgether T, Van Leuven F, Landreth GE (2005) Acute treatment with the PPARg agonist pioglitazone and ibuprofen reduces inflammation and Ab1-42 levels in APP V717I transgenic mice. Brain 128: 1442-1453.

Schütz B, Reimann J, Dumitrescu-Ozimek L, Kappes-Horn K, Landreth GE, Schürmann B, Zimmer A, Heneka MT (2005) The oral antidiabetic pioglitazone protects from neurodegeneration and ALS-like symptoms in SOD1-G93A transgenic mice. J. Neurosci. 25: 7805-7812.

Sastre M, Dewachter I, Roßner S, Bogdanovic N, Rosen E, Borghgraef P, Evert BO, Dumitrescu-Ozimek L, Thal DR, Landreth G, Walter J, Klockgether T, Van Leuven F, Heneka MT (2006) NSAIDs repress BACE1 gene promoter activity by the activation of PPARg. Proc. Natl. Acad. Sci. U.S.A. 103:443-448.

Sastre M, Dewachter I, Landreth GE, Willson TM, Klockgether T, Van Leuven F, Heneka MT (2003) Nonsteroidal anti-Inflammatory drugs and peroxisome proliferator-activated receptor-g agonists modulate immunostimulated processing of amyloid precursor protein through regulation of b-Secretase. J. Neurosci. 23: 9796-9804.

Terwel D, Steffensen KR, Verghese PB, Kummer MP, Gustafsson JÅ, Holtzman DM, Heneka MT. Critical role of astroglial apolipoprotein E and liver X receptor-α expression for microglial Aβ phagocytosis. J Neurosci. 2011 May 11;31(19):7049-59.