Deletion of M1 muscarinic acetylcholine receptors increases amyloid pathology in vitro and in vivo

Albert A. Davis, Jason J. Fritz, Jürgen Wess, James J. Lah, Allan I. Levey

Research output: Contribution to journalArticle

89 Scopus citations

Abstract

Alzheimer's disease (AD) is a progressive neurological disorder that causes dementia and poses a major public health crisis as the population ages. Aberrant processing of the amyloid precursor protein (APP) is strongly implicated as a proximal event in AD pathophysiology, but the neurochemical signals that regulate APP processing in the brain are not completely understood. Activation of muscarinic acetylcholine receptors (mAChRs) has been shown to affect APP processing and AD pathology, but less is known about the roles of specificm AChR subtypes. In this study,weusedM1 mAChR knock-out mice(M1KO)to isolate the effects of theM1 mAChR on APP processing in primary neurons and on the development of amyloid pathology in a transgenic mouse model of AD. We demonstrate that the loss of M1 mAChRs increases amyloidogenic APP processing in neurons, as evidenced by decreased agonist-regulated shedding of the neuroprotective APP ectodomain APPsα and increased production of toxic Aβ peptides. Expression of M1 mAChRs on the M1KO background rescued this phenotype, indicating that M1 mAChRs are sufficient to modulate nonamyloidogenic APP processing. In APPSwe/Ind transgenic mice, the loss ofM 1 mAChRs resulted in increased levels of brain Aβ and greater accumulation of amyloid plaque pathology. Analysis of APP metabolites in APPSwe/Ind brain tissue indicates that the loss of M1 mAChRs increases amyloidogenic APP processing. These results indicate that the M1 mAChR is an important regulator of amyloidogenesis in the brain and provide strong support for targeting theM1 mAChR as a therapeutic candidate in AD.

Original languageEnglish
Pages (from-to)4190-4196
Number of pages7
JournalJournal of Neuroscience
Volume30
Issue number12
DOIs
StatePublished - Mar 24 2010
Externally publishedYes

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