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This study was conducted to evaluate whether melatonin treatment could provide beneficial effects in an Alzheimer model related to tauopathy by improving the autophagic flux and, thereby, prevent cognitive decline. The injection of <jats:styled-content style=\"fixed-case\">AAV<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">hT<\/jats:styled-content>au<jats:sup>P301L<\/jats:sup> viral vectors and treatment\/injection with okadaic acid were used to achieve mouse and human ex vivo, and in vivo tau\u2010related models. Melatonin (10\u00a0\u03bcmol\/L) impeded oxidative stress, tau hyperphosphorylation, and cell death by restoring autophagy flux in the ex vivo models. In the in vivo studies, intracerebroventricular injection of <jats:styled-content style=\"fixed-case\">AAV<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">hT<\/jats:styled-content>au<jats:sup>P301L<\/jats:sup> increased oxidative stress, neuroinflammation, and tau hyperphosphorylation in the hippocampus 7\u00a0days after the injection, without inducing cognitive impairment; however, when animals were maintained for 28\u00a0days, cognitive decline was apparent. Interestingly, late melatonin treatment (10\u00a0mg\/kg), starting once the alterations mentioned above were established (from day 7 to day 28), reduced oxidative stress, neuroinflammation, tau hyperphosphorylation, and caspase\u20103 activation; these observations correlated with restoration of the autophagy flux and memory improvement. This study highlights the importance of autophagic dysregulation in tauopathy and how administration of pharmacological doses of melatonin, once tauopathy is initiated, can restore the autophagy flux, reduce proteinopathy, and prevent cognitive decline. We therefore propose exogenous melatonin supplementation or the development of melatonin derivatives to improve autophagy flux for the treatment of proteinopathies like AD.<\/jats:p>","DOI":"10.1111\/jpi.12578","type":"journal-article","created":{"date-parts":[[2019,4,3]],"date-time":"2019-04-03T18:23:10Z","timestamp":1554315790000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":73,"title":["Pharmacological doses of melatonin impede cognitive decline in tau\u2010related Alzheimer models, once tauopathy is initiated, by restoring the autophagic flux"],"prefix":"10.1111","volume":"67","author":[{"given":"Enrique","family":"Luengo","sequence":"first","affiliation":[{"name":"Department of Pharmacology School of Medicine Instituto Te\u00f3filo Hernando for Drug Discovery Universidad Aut\u00f3noma Madrid  Madrid 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