Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine.
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.
Heneka
Michael T
MT
Department of Neurology, Deutsches Zentrum für Neurodegenerative Erkrankungen, University of Bonn, 53105 Bonn, Germany. michael.heneka@ukb.uni-bonn.de
Nadrigny
Fabian
F
Regen
Tommy
T
Martinez-Hernandez
Ana
A
Dumitrescu-Ozimek
Lucia
L
Terwel
Dick
D
Jardanhazi-Kurutz
Daniel
D
Walter
Jochen
J
Kirchhoff
Frank
F
Hanisch
Uwe-Karsten
UK
Kummer
Markus P
MP
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008125:Locus Coeruleus / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009638:Norepinephrine / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018925:Chemokines; D016207:Cytokines; D011994:Recombinant Proteins; D009638:Norepinephrine