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Locus Ceruleus Degeneration Promotes Alzheimer Pathogenesis in Amyloid Precursor Protein 23 Transgenic Mice

Authors :
Mutiah A. Ramanathan
Michael T. Heneka
Thomas Klockgether
Wolf-Dieter Heiss
Mathias Hoehn
Magdalena Sastre
Lucia Dumitrescu-Ozimek
Norbert Galldiks
Andreas H. Jacobs
Andras Bilkei-Gorzo
Matthias Staufenbiel
Andras Zimmer
Thomas Debeir
Source :
The Journal of Neuroscience. 26:1343-1354
Publication Year :
2006
Publisher :
Society for Neuroscience, 2006.

Abstract

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 withN-(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.

Details

ISSN :
15292401 and 02706474
Volume :
26
Database :
OpenAIRE
Journal :
The Journal of Neuroscience
Accession number :
edsair.doi.dedup.....70fd74bffe52672136784077234551dd
Full Text :
https://doi.org/10.1523/jneurosci.4236-05.2006