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Author Notes:

Corresponding Author: Allan I. Levey, M.D., Ph.D. Department of Neurology, Emory University School of Medicine, Woodruff Memorial Research Building, 101 Woodruff Circle, Suite 6000, Atlanta, GA 30322, USA. alevey@emory.edu; Ph: 404-727-3143; Fax: 404-727-3999

We are grateful to Yinghong Cui, Guofu Fang, Xinping Huang, Howard Rees, and Zoe White for expert technical assistance.


Research Funding:

This work was supported by National Institutes of Health Grants NS030454 (A.I.L.) and F30 AG029731 (A.A.D.) and a predoctoral fellowship from the PhRMA Foundation (A.A.D.).


  • muscarinic acetylcholine receptor
  • β-amyloid
  • amyloid precursor protein
  • Alzheimer's disease
  • transgenic mouse
  • neurotransmitter

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


Journal Title:

Journal of Neuroscience Nursing


Volume 30, Number 12


, Pages 4190-4196

Type of Work:

Article | Post-print: After Peer Review


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 M1 mAChR knockout mice (M1KO) to isolate the effects of the M1 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 non-amyloidogenic APP processing. In APPSwe/Ind transgenic mice, the loss of M1 mAChRs resulted in increased levels of brain Aβ1-40 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 the M1 mAChR as a therapeutic candidate in AD.

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© 2010 the authors

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