Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer’s disease
Open accessAbstract
Rivastigmine (or Exelon) is a cholinesterase inhibitor, currently used as a symptomatic treatment for mild-to-moderate Alzheimer's disease (AD). Amyloid-β peptide (Aβ) generated from its precursor protein (APP) by β-secretase (or BACE1) and γ-secretase endoproteolysis. Alternative APP cleavage by α-secretase (a family of membrane-bound metalloproteases- Adamalysins) precludes the generation of toxic Aβ and yields a neuroprotective and neurotrophic secreted sAPPα fragment. Several signal transduction pathways, including protein kinase C and MAP kinase, stimulate α-secretase. We present data to suggest that rivastigmine, in addition to anticholinesterase activity, directs APP processing away from BACE1 and towards α-secretases. We treated rat neuronal PC12 cells and primary human brain (PHB) cultures with rivastigmine and the α-secretase inhibitor TAPI and assayed for levels of APP processing products and α-secretases. We subsequently treated 3×Tg (transgenic) mice with rivastigmine and harvested hippocampi to assay for levels of APP processing products. We also assayed postmortem human control, AD, and AD brains from subjects treated with rivastigmine for levels of APP metabolites. Rivastigmine dose-dependently promoted α-secretase activity by upregulating levels of ADAM-9, -10, and -17 α-secretases in PHB cultures. Co-treatment with TAPI eliminated rivastigmine-induced sAPPα elevation. Rivastigmine treatment elevated levels of sAPPα in 3×Tg mice. Consistent with these results, we also found elevated sAPPα in postmortem brain samples from AD patients treated with rivastigmine. Rivastigmine can modify the levels of several shedding proteins and directs APP processing toward the non-amyloidogenic pathway. This novel property of rivastigmine can be therapeutically exploited for disease-modifying intervention that goes beyond symptomatic treatment for AD.
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Rivastigmine is authorized for use in mild-to-moderate Parkinson's disease dementia and mild-to-moderate AD.
“It is authorized for use in mild-to-moderate Parkinson’s disease dementia and mild-to-moderate AD [116,117,118].”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [116]
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Role of Cholinergic Signaling in Alzheimer’s Disease
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Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease
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“ACh metabolism is inhibited by rivastigmine ( 3 , Figure 5), a pseudo-irreversible inhibitor of AChE and butyrylcholinesterase (BuChE) [114–116].”
BackgroundMolecular mechanisms of Alzheimer’s disease: From therapeutic targets to promising drugs
Alan, E., Kerry, Z., & Sevin, G. (2023) · Fundamental & Clinical Pharmacology · doi:10.1111/fcp.12861 · Cited by 17 · see citing works
- Authors
- Ray, B., Maloney, B., Sambamurti, K., Karnati, H. K., Nelson, P. T., Greig, N. H., & Lahiri, D. K.
- Affiliations
- Indiana University Indianapolis (US)
- Medical University of South Carolina (US)
- National Institutes of Health (US)
- University of Kentucky (US)
- Corresponding author
- Lahiri, Debomoy K.
- ORCID
- Venue
- Translational Psychiatry
- Published
- 2020-02-03
- Volume
- 10
- Issue
- 1
- Pages
- 47-47
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC7026402
- OpenAlex
- W3003708541
- Cited by
- 91
- References
- 119
- Citations by year
- 2026: 13 · 2025: 11 · 2024: 18 · 2023: 12 · 2022: 17 · 2021: 15 · 2020: 5
- FWCI
- 7.37
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-03-02)
- Open access
- gold
- doi.org
- Locations
- Translational Psychiatry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UKnowledge (University of Kentucky) (submittedVersion, cc-by)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by)
- Purdue University Indianapolis (Indiana University) (submittedVersion, cc-by)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (R01AG051086, P30AG010133)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- rivastigmine, Alzheimer's disease, alpha-secretase, APP processing, amyloid-beta, sAPPα, ADAM10, ADAM17, TAPI, cholinesterase inhibitors, non-amyloidogenic pathway, disease-modifying therapy, 3xTg-AD mice, hippocampus
- MeSH terms
- Rivastigmine, Prohibitins, Alzheimer Disease, Animals, Humans, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Mice, Rats, Amyloid Precursor Protein Secretases
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