Searching for just a few words should be enough to get started. If you need to make more complex queries, use the tips below to guide you.
Article type: Research Article
Authors: Sabbir, Mohammad Golama; b; c; * | Speth, Robert C.c; d | Albensi, Benedict C.c; e; f
Affiliations: [a] Alzo Biosciences Inc., San Diego, CA, USA | [b] St. Boniface Hospital Albrechtsen Research Centre, Canadian Centre for Agri-Food Research in Health and Medicine, Winnipeg, Manitoba, Canada | [c] Nova Southeastern University, College of Pharmacy, Fort Lauderdale, FL, USA | [d] Department of Pharmacology and Physiology, School of Medicine, Georgetown University, Washington, DC, USA | [e] St. Boniface Hospital Albrechtsen Research Centre, Division of Neurodegenerative Disorders, Winnipeg, Manitoba, Canada | [f] University of Manitoba, College of Medicine, Winnipeg, Manitoba, Canada
Correspondence: [*] Correspondence to: Mohammad Golam Sabbir, Nova Southeastern University, College of Pharmacy, Davie, FL, USA; Alzo Biosciences Inc., 7220 Trade St Ste 370, San Diego, CA, 92121-2380, USA. E-mails: [email protected], [email protected].
Abstract: Background:Dysfunction of cholinergic neurotransmission is a hallmark of Alzheimer’s disease (AD); forming the basis for using acetylcholine (ACh) esterase (AChE) inhibitors to mitigate symptoms of ACh deficiency in AD. The Cholinergic Receptor Muscarinic 1 (CHRM1) is highly expressed in brain regions impaired by AD. Previous analyses of postmortem AD brains revealed unaltered CHRM1 mRNA expression compared to normal brains. However, the CHRM1 protein level in AD and other forms of dementia has not been extensively studied. Reduced expression of CHRM1 in AD patients may explain the limited clinical efficacy of AChE inhibitors. Objective:To quantify CHRM1 protein in the postmortem hippocampus and temporal cortex of AD, Parkinson’s disease (PD), and frontotemporal dementia (FTD) patients. Methods:Western blotting was performed on postmortem hippocampus (N = 19/73/7/9: unaffected/AD/FTD/PD) and temporal cortex (N = 9/74/27: unaffected/AD/PD) using a validated anti-CHRM1 antibody. Results:Quantification based on immunoblotting using a validated anti-CHRM1 antibody revealed a significant loss of CHRM1 protein level (<50%) in the hippocampi (78% AD, 66% PD, and 85% FTD) and temporal cortices (56% AD and 42% PD) of dementia patients. Loss of CHRM1 in the temporal cortex was significantly associated with early death (<65–75 years) for both AD and PD patients. Conclusion:Severe reduction of CHRM1 in a subset of AD and PD patients can explain the reported low efficacy of AChE inhibitors as a mitigating treatment for dementia patients. Based on this study, it can be suggested that future research should prioritize therapeutic restoration of CHRM1 protein levels in cholinergic neurons.
Keywords: Alzheimer’s disease, β-arrestin, Cholinergic Receptor Muscarinic 1, CHRM1, frontotemporal dementia, Parkinson’s disease, survival
DOI: 10.3233/JAD-220766
Journal: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 727-747, 2022
IOS Press, Inc.
6751 Tepper Drive
Clifton, VA 20124
USA
Tel: +1 703 830 6300
Fax: +1 703 830 2300
[email protected]
For editorial issues, like the status of your submitted paper or proposals, write to [email protected]
IOS Press
Nieuwe Hemweg 6B
1013 BG Amsterdam
The Netherlands
Tel: +31 20 688 3355
Fax: +31 20 687 0091
[email protected]
For editorial issues, permissions, book requests, submissions and proceedings, contact the Amsterdam office [email protected]
Inspirees International (China Office)
Ciyunsi Beili 207(CapitaLand), Bld 1, 7-901
100025, Beijing
China
Free service line: 400 661 8717
Fax: +86 10 8446 7947
[email protected]
For editorial issues, like the status of your submitted paper or proposals, write to [email protected]
如果您在出版方面需要帮助或有任何建, 件至: [email protected]