The muscarinic M1 agonist xanomeline increases soluble amyloid precursor protein release from chinese hamster ovary-m1 cells
Abstract
The functionally selective M1 agonist xanomeline, which is currently undergoing clinical trials as a therapy for Alzheimer's disease, was compared to the muscarinic agonist carbachol for effects on secretion of soluble amyloid precursor protein (APPs) from Chinese hamster ovary cells transfected with the human m1 receptor (CHO-m1). Release of APPs from CHO-m1 cells was increased maximally (4-10 fold) by 100 microM carbachol (EC50 = 11 microM) and by 100 nM xanomeline (EC50 = 10 nM). Stimulation of APPs secretion by xanomeline and carbachol was blocked by preincubation with 1 microM atropine. Carbachol did not stimulate APPs secretion from non-transfected CHO cells. Pilocarpine at 1 mM also increased APPs release. The efficacy of carbachol, xanomeline and pilocarpine for stimulating APPs secretion did not differ significantly. Activation of protein kinase C (PKC) in m1 transfected cell lines by 1 microM phorbol dibutyrate (PDBu) increased APPs release, and this was inhibited 97% by the PKC inhibitor bisindolemalemide. The PKC inhibitor decreased xanomeline and carbachol-stimulated APPs secretion by only 25-30%. These results demonstrate that xanomeline increased APPs release by activation of m1 muscarinic receptors and support the possibility that cholinergic replacement therapy for Alzheimer's Disease may reduce amyloid deposition.
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Muscarinic M1 acetylcholine receptors elevate cleavage of APP by α-secretase, which lowers Aβ production and levels.
“Similarly, muscarinic M1 acetylcholine receptors elevate cleavage of APP by α-secretase, which lowers Aβ production and levels (8, 9)”
From Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans (2011) · cites this paper as [8]
M1-mediated down-regulation of Aβ acts by increasing α-secretase cleavage of APP.
“Similar to our current data with serotonin, M1-mediated down-regulation of Aβ acts by increasing α-secretase cleavage of APP (8, 9).”
From Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans (2011) · cites this paper as [8]
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- Authors
- Eckols, K., Bymaster, F. P., Mitch, C. H., Shannon, H. E., Ward, J. S., & DeLapp, N. W.
- Affiliations
- Eli Lilly (United States) (US)
- Corresponding author
- DeLapp, Neil W.
- ORCID
- Shannon, Harlan E.
- Venue
- Life Sciences
- Publisher
- Elsevier BV
- Published
- 1995-08
- Volume
- 57
- Issue
- 12
- Pages
- 1183-1190
- ISSN
- 0024-3205 (ISSN-L)
- OpenAlex
- W2062267821
- Cited by
- 53
- References
- 18
- Citations by year
- 2020: 1 · 2018: 1 · 2017: 1 · 2016: 1 · 2014: 2
- FWCI
- 3.47
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Life Sciences (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- xanomeline, M1 muscarinic receptor, APP secretion, carbachol, pilocarpine, protein kinase C, atropine, Alzheimer's disease, amyloid deposition
- MeSH terms
- Animals, Carbachol, Dose-Response Relationship, Drug, Electrophoresis, Cricetinae, Humans, Phorbols, Pyridines, Thiadiazoles, Immunoblotting, CHO Cells, Amyloid beta-Protein Precursor, Muscarinic Agonists
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