Loss of muscarinic M1 receptor exacerbates Alzheimer's disease-like pathology and cognitive decline

Rodrigo Medeiros, Masashi Kitazawa, Antonella Caccamo, David Baglietto-Vargas, Tatiana Estrada-Hernandez, David H. Cribbs, Avraham Fisher, Frank M. Laferla

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

Alzheimer's disease (AD) is pathologically characterized by tau-laden neurofibrillary tangles and β-amyloid deposits. Dysregulation of cholinergic neurotransmission has been implicated in AD pathogenesis, contributing to the associated memory impairments; yet, the exact mechanisms remain to be defined. Activating the muscarinic acetylcholine M1 receptors (M1Rs) reduces AD-like pathological features and enhances cognition in AD transgenic models. To elucidate the molecular mechanisms by which M1Rs affect AD pathophysiological features, we crossed the 3xTgAD and transgenic mice expressing human Swedish, Dutch, and Iowa triple-mutant amyloid precursor protein (Tg-SwDI), two widely used animal models, with the M1R-/- mice. Our data show that M 1R deletion in the 3xTgAD and Tg-SwDI mice exacerbates the cognitive impairment through mechanisms dependent on the transcriptional dysregulation of genes required for memory and through acceleration of AD-related synaptotoxicity. Ablating the M1R increased plaque and tangle levels in the brains of 3xTgAD mice and elevated cerebrovascular deposition of fibrillar Aβ in Tg-SwDI mice. Notably, tau hyperphosphorylation and potentiation of amyloidogenic processing in the mice with AD lacking M 1R were attributed to changes in the glycogen synthase kinase 3β and protein kinase C activities. Finally, deleting the M1R increased the astrocytic and microglial response associated with Aβ plaques. Our data highlight the significant role that disrupting the M1R plays in exacerbating AD-related cognitive decline and pathological features and provide critical preclinical evidence to justify further development and evaluation of selective M1R agonists for treating AD.

Original languageEnglish (US)
Pages (from-to)980-991
Number of pages12
JournalAmerican Journal of Pathology
Volume179
Issue number2
DOIs
StatePublished - Aug 1 2011

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Medeiros, R., Kitazawa, M., Caccamo, A., Baglietto-Vargas, D., Estrada-Hernandez, T., Cribbs, D. H., Fisher, A., & Laferla, F. M. (2011). Loss of muscarinic M1 receptor exacerbates Alzheimer's disease-like pathology and cognitive decline. American Journal of Pathology, 179(2), 980-991. https://doi.org/10.1016/j.ajpath.2011.04.041