{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T00:10:12Z","timestamp":1791591012072,"version":"4.3.4"},"reference-count":42,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2013,3,24]],"date-time":"2013-03-24T00:00:00Z","timestamp":1364083200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2013,6]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>Accumulation of tau is a critical event in several neurodegenerative disorders, collectively known as tauopathies, which include Alzheimer's disease and frontotemporal dementia. Pathological tau is hyperphosphorylated and aggregates to form neurofibrillary tangles. The molecular mechanisms leading to tau accumulation remain unclear and more needs to be done to elucidate them. Age is a major risk factor for all tauopathies, suggesting that molecular changes contributing to the aging process may facilitate tau accumulation and represent common mechanisms across different tauopathies. Here, we use multiple animal models and complementary genetic and pharmacological approaches to show that the mammalian target of rapamycin (<jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content>) regulates tau phosphorylation and degradation. Specifically, we show that genetically increasing <jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content> activity elevates endogenous mouse tau levels and phosphorylation. Complementary to it, we further demonstrate that pharmacologically reducing <jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content> signaling with rapamycin ameliorates tau pathology and the associated behavioral deficits in a mouse model overexpressing mutant human tau. Mechanistically, we provide compelling evidence that the association between <jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content> and tau is linked to GSK3\u03b2 and autophagy function. In summary, we show that increasing <jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content> signaling facilitates tau pathology, while reducing <jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content> signaling ameliorates tau pathology. Given the overwhelming evidence that reducing <jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content> signaling increases lifespan and healthspan, the data presented here have profound clinical implications for aging and tauopathies and provide the molecular basis for how aging may contribute to tau pathology. Additionally, these results provide preclinical data indicating that reducing <jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content> signaling may be a valid therapeutic approach for tauopathies.<\/jats:p>","DOI":"10.1111\/acel.12057","type":"journal-article","created":{"date-parts":[[2013,2,20]],"date-time":"2013-02-20T22:00:50Z","timestamp":1361397650000},"page":"370-380","source":"Crossref","is-referenced-by-count":341,"title":["<scp>mTOR<\/scp> regulates tau phosphorylation and degradation: implications for Alzheimer's disease and other tauopathies"],"prefix":"10.1111","volume":"12","author":[{"given":"Antonella","family":"Caccamo","sequence":"first","affiliation":[{"name":"Department of Physiology and The Barshop Institute for Longevity and Aging Studies University of Texas Health Science Center at San Antonio 7703 Floyd Curl Drive San Antonio TX 78229 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Magr\u00ec","sequence":"additional","affiliation":[{"name":"Department of Physiology and The Barshop Institute for Longevity and Aging Studies University of Texas Health Science Center at San Antonio 7703 Floyd Curl Drive San Antonio TX 78229 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David X.","family":"Medina","sequence":"additional","affiliation":[{"name":"Department of Physiology and The Barshop Institute for Longevity and Aging Studies University of Texas Health Science Center at San Antonio 7703 Floyd Curl Drive San Antonio TX 78229 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena V.","family":"Wisely","sequence":"additional","affiliation":[{"name":"Department of Physiology and The Barshop Institute for Longevity and Aging Studies University of Texas Health Science Center at San Antonio 7703 Floyd Curl Drive San Antonio TX 78229 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel F.","family":"L\u00f3pez\u2010Aranda","sequence":"additional","affiliation":[{"name":"Departments of Neurobiology Psychiatry and Biobehavioral Sciences Psychology and the Brain Research Institute University of California, Los Angeles 695 Charles E. Young Dr South Los Angeles CA 90095 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alcino J.","family":"Silva","sequence":"additional","affiliation":[{"name":"Departments of Neurobiology Psychiatry and Biobehavioral Sciences Psychology and the Brain Research Institute University of California, Los Angeles 695 Charles E. Young Dr South Los Angeles CA 90095 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Oddo","sequence":"additional","affiliation":[{"name":"Department of Physiology and The Barshop Institute for Longevity and Aging Studies University of Texas Health Science Center at San Antonio 7703 Floyd Curl Drive San Antonio TX 78229 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