[en] 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.
Disciplines :
Neurology
Author, co-author :
HENEKA, Michael ; Department of Neurology, Deutsches Zentrum für Neurodegenerative Erkrankungen, University of Bonn, 53105 Bonn, Germany. michael.heneka@ukb.uni-bonn.de
Nadrigny, Fabian; Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany
Regen, Tommy; Institute of Neuropathology, University of Göttingen, 37075 Göttingen, Germany
Martinez-Hernandez, Ana; Max Planck Institute of Biophysical Chemistry, 37077 Göttingen, Germany
Dumitrescu-Ozimek, Lucia; Deutsches Zentrum für Neurodegenerative Erkrankungen, Department of Neurology, University of Bonn, 53105 Bonn, Germany
Terwel, Dick; Deutsches Zentrum für Neurodegenerative Erkrankungen, Department of Neurology, University of Bonn, 53105 Bonn, Germany
Walter, Jochen; Deutsches Zentrum für Neurodegenerative Erkrankungen, Department of Neurology, University of Bonn, 53105 Bonn, Germany
Kirchhoff, Frank; Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany ; Molecular Physiology, Institute of Physiology, University of Saarland, 66421 Homburg/Saar, Germany
Hanisch, Uwe-Karsten; Institute of Neuropathology, University of Göttingen, 37075 Göttingen, Germany
Kummer, Markus P; Deutsches Zentrum für Neurodegenerative Erkrankungen, Department of Neurology, University of Bonn, 53105 Bonn, Germany
External co-authors :
yes
Language :
English
Title :
Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine.
Publication date :
30 March 2010
Journal title :
Proceedings of the National Academy of Sciences of the United States of America
ISSN :
0027-8424
eISSN :
1091-6490
Publisher :
Proceedings of the National Academy of Sciences, United States
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