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

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 M(1) receptors (M(1)Rs) reduces AD-like pathological features and enhances cognition in AD transgenic models. To elucidate the molecular mechanisms by which M(1)Rs 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 M(1)R(-/-) mice. Our data show that M(1)R 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 M(1)R 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(1)R were attributed to changes in the glycogen synthase kinase 3β and protein kinase C activities. Finally, deleting the M(1)R increased the astrocytic and microglial response associated with Aβ plaques. Our data highlight the significant role that disrupting the M(1)R plays in exacerbating AD-related cognitive decline and pathological features and provide critical preclinical evidence to justify further development and evaluation of selective M(1)R agonists for treating AD.

• Authors: Rodrigo Medeiros, Masashi Kitazawa, Antonella Caccamo, David Baglietto-Vargas, Tatiana Estrada-Hernandez, David H Cribbs, Avraham Fisher, Frank M LaFerla
• Journal: The American journal of pathology (Am J Pathol) Vol. 179 Issue 2 Pg. 980-91 (Aug 2011) ISSN: 1525-2191 [Electronic] United States
• PMID: 21704011 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Receptor, Muscarinic M1

Topics

• Alzheimer Disease (metabolism)
• Amyloid beta-Peptides (metabolism)
• Animals
• Cognition
• Cognition Disorders (metabolism)
• Conditioning, Psychological
• Heterozygote
• Homozygote
• Immunohistochemistry (methods)
• Male
• Maze Learning
• Memory
• Mice
• Mice, Knockout
• Mice, Transgenic
• Pattern Recognition, Visual
• Receptor, Muscarinic M1 (genetics, physiology)