Noradrenaline deficiency in brain increases beta-amyloid plaque burden in an animal model of Alzheimer's disease.
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.
Kalinin
Sergey
S
Department of Anesthesiology, University of Illinois, & Jesse Brown Veteran's Affairs Research Division, Chicago, IL 60612, United States.
Gavrilyuk
Vitaliy
V
Polak
Paul E
PE
Vasser
Robert
R
Zhao
Jie
J
Heneka
Michael T
MT
Feinstein
Douglas L
DL
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001596:Benzylamines / Q000633:toxicity; D001921:Brain / Q000473:pathology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008125:Locus Coeruleus / Q000187:drug effects / Q000293:injuries / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D015260:Neprilysin / Q000378:metabolism; D014179:Neurotransmitter Uptake Inhibitors / Q000633:toxicity; D009638:Norepinephrine / Q000172:deficiency* / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects; D058225:Plaque, Amyloid / Q000187:drug effects / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D001596:Benzylamines; D014179:Neurotransmitter Uptake Inhibitors; D015260:Neprilysin; D007545:Isoproterenol; C012102:DSP 4; D009638:Norepinephrine