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Amyloid-\u03b2 peptide (A\u03b2) generated from its precursor protein (APP) by \u03b2-secretase (or BACE1) and \u03b3-secretase endoproteolysis. Alternative APP cleavage by \u03b1-secretase (a family of membrane-bound metalloproteases\u2013 Adamalysins) precludes the generation of toxic A\u03b2 and yields a neuroprotective and neurotrophic secreted sAPP\u03b1 fragment. Several signal transduction pathways, including protein kinase C and MAP kinase, stimulate \u03b1-secretase. We present data to suggest that rivastigmine, in addition to anticholinesterase activity, directs APP processing away from BACE1 and towards \u03b1-secretases. We treated rat neuronal PC12 cells and primary human brain (PHB) cultures with rivastigmine and the \u03b1-secretase inhibitor TAPI and assayed for levels of APP processing products and \u03b1-secretases. We subsequently treated 3\u00d7Tg (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 \u03b1-secretase activity by upregulating levels of ADAM-9, -10, and -17 \u03b1-secretases in PHB cultures. Co-treatment with TAPI eliminated rivastigmine-induced sAPP\u03b1 elevation. Rivastigmine treatment elevated levels of sAPP\u03b1 in 3\u00d7Tg mice. Consistent with these results, we also found elevated sAPP\u03b1 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.<\/jats:p>","DOI":"10.1038\/s41398-020-0709-x","type":"journal-article","created":{"date-parts":[[2020,2,17]],"date-time":"2020-02-17T15:06:30Z","timestamp":1581951990000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":75,"title":["Rivastigmine modifies the \u03b1-secretase pathway and potentially early Alzheimer\u2019s disease"],"prefix":"10.1038","volume":"10","author":[{"given":"Balmiki","family":"Ray","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2364-9649","authenticated-orcid":false,"given":"Bryan","family":"Maloney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kumar","family":"Sambamurti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanuma K.","family":"Karnati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter T.","family":"Nelson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel H.","family":"Greig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1664-5933","authenticated-orcid":false,"given":"Debomoy K.","family":"Lahiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,2,3]]},"reference":[{"key":"709_CR1","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.jalz.2018.02.001","volume":"14","author":"Alzheimer\u2019s Association.","year":"2018","unstructured":"Alzheimer\u2019s Association. 2018 Alzheimer\u2019s disease facts and figures. 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He also has stock options from QR Pharma for patents or patents pending on AIT-082, Memantine, Acamprosate, and GILZ analogues. All have no direct influence on the research presented here. B.R., B.M., K.S., H.K.K., P.T.N., N.H.G. have nothing to declare.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"All procedures were approved and overseen by the Institutional Biosafety. Committee (IBC), Office of Research Compliance, Indiana University, and Indianapolis, IN, USA. All experiments that used animals were reviewed and approved before initiation by the Institutional Animal Care and Use Committee (IACUC) of the Intramural Research Program, National Institute on Aging (Protocol No. 331-TGB-2021), which monitored all processes for compliance with appropriate regulatory and ethical standards.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}],"article-number":"47"}}