title: Impaired coupling of muscarinic M1 receptors to G-proteins in the neocortex is associated with severity of dementia in Alzheimer's disease.
abstract: 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.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, National University of Singapore, Singapore.
authors.forename: Shirley W Y
authors.initials: SW
authors.lastname: Tsang
authors.forename: Mitchell K P
authors.initials: MK
authors.lastname: Lai
authors.forename: Sara
authors.initials: S
authors.lastname: Kirvell
authors.forename: Paul T
authors.initials: PT
authors.lastname: Francis
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Esiri
authors.forename: Tony
authors.initials: T
authors.lastname: Hope
authors.forename: Christopher P L-H
authors.initials: CP
authors.lastname: Chen
authors.forename: Peter T-H
authors.initials: PT
authors.lastname: Wong
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology* / Q000503:physiopathology*; D000704:Analysis of Variance; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003072:Cognition Disorders / Q000209:etiology / Q000378:metabolism; D003704:Dementia / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D019204:GTP-Binding Proteins / Q000502:physiology*; D006801:Humans; D008297:Male; D018727:Muscarinic Antagonists / Q000493:pharmacokinetics; D019579:Neocortex / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D010890:Pirenzepine / Q000493:pharmacokinetics; D011180:Postmortem Changes; D011485:Protein Binding / Q000187:drug effects; D011569:Psychiatric Status Rating Scales; D043643:Receptor, Muscarinic M1 / Q000502:physiology*; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D018727:Muscarinic Antagonists; D043643:Receptor, Muscarinic M1; D014316:Tritium; D010890:Pirenzepine; D002795:Choline O-Acetyltransferase; D019204:GTP-Binding Proteins