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Muscarinic M1 Receptor Coupling to G-protein is Intact in Parkinson's Disease Dementia

Lookup NU author(s): Professor Raj KalariaORCiD


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Background: Postsynaptic cholinergic deficits, including reduced cortical muscarinic M1 receptor coupling to G-proteins, are neurochemical findings postulated to underlie the limited efficacy of presynaptically-targeted cholinergic replacement therapies in Alzheimer's disease (AD). While the loss of M1-G-protein coupling has been associated with beta-amyloid (A beta) burden in AD, the status of M1 coupling to G-proteins in Parkinson's disease-related or mixed dementias is unclear.Objective: To test the hypothesis that M1 receptor uncoupling is correlated with A beta burden, we aimed to study muscarinic M1 neurochemical parameters in neurodegenerative dementias characterized by low and high A beta loads.Methods: M1 receptors, M1 coupling to G-proteins as well as A beta were measured in postmortem frontal cortex of a cohort of longitudinally assessed patients with Parkinson's Disease Dementia (PDD, low A beta load) and AD with significant subcortical cerebrovascular disease (AD + CVD, high A beta load). Results: We found unchanged levels of M1 receptors in both dementia groups, while M1 coupling was reduced only in AD + CVD (p < 0.01). Furthermore, A beta concentration was significantly increased only in AD + CVD, and correlated negatively with M1-G-protein coupling in the dementia groups.Conclusions: Our study suggests that loss ofM1coupling to G-proteins may be a neurochemical feature of neurodegenerative dementias with high cortical A beta burden, and that cholinergic replacement therapies may be more efficacious for PDD due to low A beta burden.

Publication metadata

Author(s): Lee JH, Francis PT, Ballard CG, Aarsland D, Kalaria RN, Wong PTH, Chen CP, Lai MKP

Publication type: Article

Publication status: Published

Journal: Journal of Parkinsons Disease

Year: 2016

Volume: 6

Issue: 4

Pages: 733-739

Online publication date: 19/10/2016

Acceptance date: 13/09/2016

ISSN (print): 1877-7171

ISSN (electronic): 1877-718X

Publisher: IOS Press


DOI: 10.3233/JPD-160932


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Funder referenceFunder name
Alzheimer's Research UK
Alzheimer's Society
London Neurodegenerative Diseases Brain Bank - MRC
NIHR Newcastle Biomedical Research Centre and Unit
G0400074UK Medical Research Council
NMRC/CSA/032/2011National Medical Research Council in Singapore