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We have previously demonstrated that Sirt3 gene deletion leads to brain mitochondrial dysfunction and neuroinflammation. We also reported that silencing of Sirt3 gene in APP\/PS1 mice results in exacerbation of insulin resistance, neuroinflammation and \u03b2 amyloid plaque deposition. To further understand how metabolic syndrome and amyloid pathology interact, we performed RNA-seq analysis of the brain samples of APP\/PS1\/Sirt3<jats:sup>-\/-<\/jats:sup> mice. Gene expression patterns were modulated in metabolic and inflammatory pathways by Sirt3 gene deletion, amyloid pathology, and the combination. Following Sirt3 gene deletion, a key finding was the decreased expression of insulin-degrading enzyme (IDE), an enzyme that regulates the levels of insulin and A\u03b2 peptides. Western diet feeding of Sirt3<jats:sup>-\/-<\/jats:sup> and APP\/PS1 mice resulted in decrease of IDE protein, parallel to Sirt3 downregulation. Conversely, activation of SIRT3 by nicotinamide riboside in vivo and in vitro resulted in IDE upregulation. SIRT3 activation in vivo also increased the levels of neprilysin, another A\u03b2 degrading enzyme and decreased the levels of BACE1 which generates A\u03b2 peptide suggesting SIRT3\u2019s role in amyloid plaque reduction. Our findings provide a plausible mechanism linking metabolic syndrome and amyloid pathology. SIRT3 may be a potential therapeutic target to treat AD.<\/jats:p>","DOI":"10.1038\/s41598-022-23652-5","type":"journal-article","created":{"date-parts":[[2022,11,17]],"date-time":"2022-11-17T21:02:36Z","timestamp":1668718956000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Sirt3 deficiency induced down regulation of insulin degrading enzyme in comorbid Alzheimer\u2019s disease with metabolic syndrome"],"prefix":"10.1038","volume":"12","author":[{"given":"Alpna","family":"Tyagi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Musa","family":"Musa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wladimir","family":"Labeikovsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subbiah","family":"Pugazhenthi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,11,17]]},"reference":[{"key":"23652_CR1","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1186\/s12933-017-0647-y","volume":"17","author":"MJ Gurka","year":"2018","unstructured":"Gurka, M. 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