Cited by 91Alzheimer's disease research and treatmentsCholinesterase and Neurodegenerative DiseasesDementia and Cognitive Impairment Research

Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer’s disease

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Ray, Balmiki, Maloney, Bryan, Sambamurti, Kumar, Karnati, Hanuma K., Nelson, Peter T., Greig, Nigel H., Lahiri, Debomoy K.·2020·Translational Psychiatry

Abstract

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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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.
Venue
Translational Psychiatry
Published
2020-02-03
Volume
10
Issue
1
Pages
47-47
ISSN
2158-3188 (ISSN-L)
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
Open access
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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