Impaired coupling of muscarinic M1 receptors to G-proteins in the neocortex is associated with severity of dementia in Alzheimer's disease

Impaired transmission of acetylcholine-mediated signaling by postsynaptic muscarinic M, 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 M-1 receptors and dementia severity has not been demonstrated. The present study aims to measure M, 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 M, receptor density, M-1/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 M-1 receptor densities were unchanged in AD, which contrasted with significantly reduced M-1 coupling to G-proteins in severely demented AD patients. Loss of M-1/G-protein coupling in the frontal cortex, but not the temporal cortex, also correlated with the rate of cognitive decline. Additionally, correlations between M-1/G-protein coupling and ChAT activities were demonstrated in both regions. These results suggest that defective coupling of neocortical M, 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 M-1/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. (c) 2005 Elsevier Inc. All rights reserved.