Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice.
Locus ceruleus (LC) degeneration and loss of cortical noradrenergic innervation occur early in Alzheimer's disease (AD). Although this has been known for several decades, the contribution of LC degeneration to AD pathogenesis remains unclear. We induced LC degeneration with N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (dsp4) in amyloid precursor protein 23 (APP23) transgenic mice with a low amyloid load. Then 6 months later the LC projection areas showed a robust elevation of glial inflammation along with augmented amyloid plaque deposits. Moreover, neurodegeneration and neuronal loss significantly increased. Importantly, the paraventricular thalamus, a nonprojection area, remained unaffected. Radial arm maze and social partner recognition tests revealed increased memory deficits while high-resolution magnetic resonance imaging-guided micro-positron emission tomography demonstrated reduced cerebral glucose metabolism, disturbed neuronal integrity, and attenuated acetylcholinesterase activity. Nontransgenic mice with LC degeneration were devoid of these alterations. Our data demonstrate that the degeneration of LC affects morphology, metabolism, and function of amyloid plaque-containing higher brain regions in APP23 mice. We postulate that LC degeneration substantially contributes to AD development.
Heneka
Michael T
MT
Department of Neurology, University of Bonn, 53127 Bonn, Germany. heneka@uni-muenster.de
Ramanathan
Mutiah
M
Jacobs
Andreas H
AH
Dumitrescu-Ozimek
Lucia
L
Bilkei-Gorzo
Andras
A
Debeir
Thomas
T
Sastre
Magdalena
M
Galldiks
Norbert
N
Zimmer
Andreas
A
Hoehn
Mathias
M
Heiss
Wolf-Dieter
WD
Klockgether
Thomas
T
Staufenbiel
Matthias
M
D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000209:etiology / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging; D003072:Cognition Disorders / Q000209:etiology; D005260:Female; D008125:Locus Coeruleus / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D009410:Nerve Degeneration / Q000473:pathology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism; D058225:Plaque, Amyloid / Q000473:pathology; D049268:Positron-Emission Tomography; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D050494:Vesicular Acetylcholine Transport Proteins; D030421:Peroxynitrous Acid; D052247:Nitric Oxide Synthase Type II; D009638:Norepinephrine