Another experimental focus is the modulation of inflammatory processes by neurotransmitters. Noradrenaline (NA) acts as a potent suppressor of glial inflammation. Previously we have shown that the chemical removal of the locus ceruleus (LC), which serves as the main source of NA for its projection areas of the hippocampus and cortex, the amyloid-β (Aβ)-induced cortical inflammation potentiates (1). NA acts here on the reduction of IkB protein and a consecutive increase in NFkB-mediated transcription of proinflammatory genes (2). Since the LC degenerates early in the course of AD, the resulting decrease of NA in the hippocampus and cortex could facilitate the inflammatory response to Aβ-plaque deposition. We have shown that LC degeneration leads to increased Aβ plaque formation and cell loss (3). This suggests that increased inflammation contributes to neuronal dysfunction and cell death in AD. The influence of NA on the inflammation and neurodegeneration in knock-out mice is being examined: in addition to Aβ plaque formation we expect either an increased NA concentration (gene knock-out of NA transporter) due to defective NA reuptake or no NA by DBH (dopamine β-hydroxylase) gene knock-out.

Selected Publications:

  1. M.T. Heneka, E. Galea, V. Gavriluyk, L. Dumitrescu-Ozimek, J. Daeschner, M.K. O´Banion, T. Klockgether and D.L. Feinstein (2002) Noradrenergic depletion potentiates b-amyloid induced cortical inflammation: Implications for Alzheimer’s disease. J. Neurosci. 22: 2434-2442.
  2. M.T. Heneka, V. Gavrilyuk, G.E. Landreth, M.K. O`Banion, G. Weinberg and D.L. Feinstein (2003) PPARγ agonists reduce β-amyloid induced cortical inflammation by increasing IκB and HSP70 expression (J. Neurochem., 85: 387-398).
  3. Locus ceruleus controls Alzheimer disease pathology by modulating microglial functions through norepinephrine. Heneka MT, Nadrigny F, Regen F, Martinez-Hernandez A, Dumitrescu-Ozimek L, Terwel D, Jardanhazi-Kurutz D, Walter J, Kirchhoff F, Hanisch UK and Kummer MP. Proc Natl Acad Sci U S A. 2010. PMID: 20231476
  4. Glial cells in (patho)physiology. Parpura V, Heneka MT, Montana V, Oliet SH, Schousboe A, Haydon PG, Stout RF Jr, Spray DC, Reichenbach A, Pannicke T, Pekny M, Pekna M, Zorec R, Verkhratsky A. J Neurochem. 2012 Jan 17. PMID: 22251135
  5. NOS2 derived nitric oxide decreases the enzymatic activity of insulin degrading enzyme in APP/PS1 mice. Kummer, MP, Hülsmann, C, Hermes, M, Axt, D and Heneka, MT J Neuroimmune Pharmacol., 2012 Jan 8. PMID: 22227962
  6. Distinct adrenergic system changes and neuroinflammation in response to induced locus ceruleus degeneration in APP/PS1 transgenic mice. Jardanhazi-Kurutz D, Kummer MP, Terwel D, Vogel K, Thiele A, Heneka MT. Neuroscience. 2011 Mar 10;176:396-407. Epub 2010 Dec 1. PMID: 21129451
  7. Selective Loss of Noradrenaline Exacerbates Early Cognitive Dysfunction and Synaptic Deficits in APP/PS1 Mice. Hammerschmidt T, Kummer MP, Terwel D, Martinez A, Gorji A, Pape HC, Rommelfanger KS, Schroeder JP, Stoll M, Schultze J, Weinshenker D, Heneka MT. Biol. Psychiatry 2012 Aug 9. PMID: 22883210

Funding