Deletion of M1Muscarinic Acetylcholine Receptors Increases Amyloid PathologyIn VitroandIn Vivo

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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 specific mAChR subtypes. In this study, we used M1mAChR knock-out mice (M1KO) to isolate the effects of the M1mAChR 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 M1mAChRs 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 M1mAChRs on the M1KO background rescued this phenotype, indicating that M1mAChRs are sufficient to modulate nonamyloidogenic APP processing. In APPSwe/Indtransgenic mice, the loss of M1mAChRs resulted in increased levels of brain Aβ and greater accumulation of amyloid plaque pathology. Analysis of APP metabolites in APPSwe/Indbrain tissue indicates that the loss of M1mAChRs increases amyloidogenic APP processing. These results indicate that the M1mAChR is an important regulator of amyloidogenesis in the brain and provide strong support for targeting the M1mAChR as a therapeutic candidate in AD.