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Impaired transmission of acetylcholine-mediated signaling by postsynaptic muscarinic M1 receptors has been postulated to underlie the limited efficacy of cholinergic replacement therapies in Alzheimer's disease (AD). However, a clear relationship between the functionality of M1 receptors and dementia severity has not been demonstrated. The present study aims to measure M1 coupling to its nucleotide binding (G-) protein in the AD neocortex, and to correlate neurochemical findings with clinical features. A cohort of dementia patients was longitudinally assessed for cognitive decline, with postmortem neuropathological confirmation of AD diagnosis. Measures of M1 receptor density, M1/G-protein coupling and choline acetyltransferase (ChAT) activities were performed in the frontal and temporal cortex of 24 AD patients as well as in 12 age-matched controls. We found that M1 receptor densities were unchanged in AD, which contrasted with significantly reduced M1 coupling to G-proteins in severely demented AD patients. Loss of M1/G-protein coupling in the frontal cortex, but not the temporal cortex, also correlated with the rate of cognitive decline. Additionally, correlations between M1/G-protein coupling and ChAT activities were demonstrated in both regions. These results suggest that defective coupling of neocortical M1 receptors to G-proteins is a neurochemical substrate of cognitive decline in AD. Based on its associations with ChAT deficits and dementia severity, we propose that M1/G-protein uncoupling may have a significant role in the disease mechanism of AD and thus may be considered to be a potential therapeutic target.

Original publication

DOI

10.1016/j.neurobiolaging.2005.07.010

Type

Journal article

Journal

Neurobiol Aging

Publication Date

09/2006

Volume

27

Pages

1216 - 1223

Keywords

Aged, Aged, 80 and over, Alzheimer Disease, Analysis of Variance, Brain Chemistry, Choline O-Acetyltransferase, Cognition Disorders, Dementia, Dose-Response Relationship, Drug, Female, GTP-Binding Proteins, Humans, Male, Muscarinic Antagonists, Neocortex, Pirenzepine, Postmortem Changes, Protein Binding, Psychiatric Status Rating Scales, Receptor, Muscarinic M1, Tritium