Muscarinic M1 Receptor Coupling to G-protein is Intact in Parkinson's Disease Dementia.
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 β-amyloid (Aβ) burden in AD, the status of M1 coupling to G-proteins in Parkinson's disease-related or mixed dementias is unclear.



To test the hypothesis that M1 receptor uncoupling is correlated with Aβ burden, we aimed to study muscarinic M1 neurochemical parameters in neurodegenerative dementias characterized by low and high Aβ loads.



M1 receptors, M1 coupling to G-proteins as well as Aβ were measured in postmortem frontal cortex of a cohort of longitudinally assessed patients with Parkinson's Disease Dementia (PDD, low Aβ load) and AD with significant subcortical cerebrovascular disease (AD + CVD, high Aβ load).



We found unchanged levels of M1 receptors in both dementia groups, while M1 coupling was reduced only in AD + CVD (p < 0.01). Furthermore, Aβ concentration was significantly increased only in AD + CVD, and correlated negatively with M1-G-protein coupling in the dementia groups.



Our study suggests that loss of M1 coupling to G-proteins may be a neurochemical feature of neurodegenerative dementias with high cortical Aβ burden, and that cholinergic replacement therapies may be more efficacious for PDD due to low Aβ burden.
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge, Singapore.
Jasinda H
JH
Lee
Wolfson Centre for Age-Related Diseases, King's College London, London, UK.
Paul T
PT
Francis
Wolfson Centre for Age-Related Diseases, King's College London, London, UK.
Clive G
CG
Ballard
Department Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Clinical Geriatrics, Karolinska Institutet, Stockholm, Sweden.
Dag
D
Aarsland
Institute for Neuroscience, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK.
Raj N
RN
Kalaria
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge, Singapore.
Peter T-H
PT
Wong
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge, Singapore.|Memory, Aging and Cognition Centre, National University Health System, Kent Ridge, Singapore.
Christopher P
CP
Chen
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge, Singapore.|Wolfson Centre for Age-Related Diseases, King's College London, London, UK.|Memory, Aging and Cognition Centre, National University Health System, Kent Ridge, Singapore.
Mitchell K P
MK
Lai
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D003704:Dementia / Q000378:metabolism* / Q000473:pathology; D015140:Dementia, Vascular / Q000378:metabolism / Q000473:pathology; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism* / Q000473:pathology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D043643:Receptor, Muscarinic M1 / Q000378:metabolism*
D043643:Receptor, Muscarinic M1; D019204:GTP-Binding Proteins
Alzheimer’s Disease; G-protein coupling; Parkinson’s Disease Dementia; cerebrovascular disease; muscarinic M1 receptors; β-amyloid