Please use this identifier to cite or link to this item: https://doi.org/10.1016/j.neurobiolaging.2005.07.010
Title: Impaired coupling of muscarinic M-1 receptors to G-proteins in the neocortex is associated with severity of dementia in Alzheimer's disease
Authors: Tsang, Shirley WY 
Lai, Mitchell KP 
Kirvell, Sara
Francis, Paul T
Esiri, Margaret M
Hope, Tony
Chen, Christopher PL-H 
Wong, Peter T-H 
Keywords: Science & Technology
Life Sciences & Biomedicine
Geriatrics & Gerontology
Neurosciences
Neurosciences & Neurology
muscarinic receptors
G-proteins
Alzheimer's disease
cognition
CHOLINE-ACETYLTRANSFERASE
ENTORHINAL CORTEX
SENILE DEMENTIA
TEMPORAL-LOBE
KINASE-C
BINDING
NEUROFIBRILLARY
ABNORMALITIES
THERAPIES
NEURONS
Issue Date: 1-Sep-2006
Publisher: ELSEVIER SCIENCE INC
Citation: Tsang, Shirley WY, Lai, Mitchell KP, Kirvell, Sara, Francis, Paul T, Esiri, Margaret M, Hope, Tony, Chen, Christopher PL-H, Wong, Peter T-H (2006-09-01). Impaired coupling of muscarinic M-1 receptors to G-proteins in the neocortex is associated with severity of dementia in Alzheimer's disease. NEUROBIOLOGY OF AGING 27 (9) : 1216-1223. ScholarBank@NUS Repository. https://doi.org/10.1016/j.neurobiolaging.2005.07.010
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. © 2005 Elsevier Inc. All rights reserved.
Source Title: NEUROBIOLOGY OF AGING
URI: https://scholarbank.nus.edu.sg/handle/10635/188372
ISSN: 01974580
15581497
DOI: 10.1016/j.neurobiolaging.2005.07.010
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