{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T03:07:44Z","timestamp":1791169664400,"version":"4.1.0"},"reference-count":73,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2014,12,27]],"date-time":"2014-12-27T00:00:00Z","timestamp":1419638400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100004192","name":"NSTDA","doi-asserted-by":"crossref","award":["P-10-11285"],"award-info":[{"award-number":["P-10-11285"]}],"id":[{"id":"10.13039\/501100004192","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004156","name":"Mahidol University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004156","id-type":"DOI","asserted-by":"crossref"}]},{"name":"CNRS"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Pineal Research"],"published-print":{"date-parts":[[2015,3]]},"abstract":"Abstract<\/jats:title>\n \n Melatonin controls many physiological functions including regulation of the circadian rhythm and clearance of free radicals and neuroprotection. Importantly, melatonin levels strongly decrease as we age and patients with Alzheimer's disease (\n AD<\/jats:styled-content>\n ) display lower melatonin than age\u2010matched controls. Several studies have reported that melatonin can reduce aggregation and toxicity of amyloid\u2010\n \u03b2<\/jats:italic>\n peptides that are produced from the\n \u03b2<\/jats:italic>\n \u2010amyloid precursor protein (\n \u03b2<\/jats:italic>\n APP<\/jats:styled-content>\n ). However, whether melatonin can directly regulate the\n \u03b2<\/jats:italic>\n APP<\/jats:styled-content>\n \u2010cleaving proteases (\u2018secretases\u2019) has not been investigated so far. In this study, we establish that melatonin stimulates the \u03b1\u2010secretase cleavage of\n \u03b2<\/jats:italic>\n APP<\/jats:styled-content>\n in cultured neuronal and non\u2010neuronal cells. This effect is fully reversed by\n ADAM<\/jats:styled-content>\n 10\u2010 and\n ADAM<\/jats:styled-content>\n 17\u2010specific inhibitors and requires both plasma membrane\u2010located melatonin receptor activation, and\n ERK<\/jats:styled-content>\n 1\/2 phosphorylation. Moreover, we demonstrate that melatonin upregulates both\n ADAM<\/jats:styled-content>\n 10 and\n ADAM<\/jats:styled-content>\n 17 catalytic activities and endogenous protein levels. Importantly, genetic depletion of one or the other protease in mouse embryonic fibroblasts prevents melatonin stimulating constitutive and\n PKC<\/jats:styled-content>\n \u2010regulated\n sAPP<\/jats:styled-content>\n \u03b1 secretion and\n ADAM<\/jats:styled-content>\n 10\/\n ADAM<\/jats:styled-content>\n 17 catalytic activities. Furthermore, we show that melatonin induces\n ADAM<\/jats:styled-content>\n 10 and\n ADAM<\/jats:styled-content>\n 17 promoter transactivation, and we identify the targeted promoter regions. Finally, we correlate melatonin\u2010dependent\n sAPP<\/jats:styled-content>\n \u03b1 production with a protection against staurosporine\u2010induced apoptosis. Altogether, our results provide the first demonstration that melatonin upregulates the nonamyloidogenic\n ADAM<\/jats:styled-content>\n 10 and\n ADAM<\/jats:styled-content>\n 17 proteases through melatonin receptor activation,\n ERK<\/jats:styled-content>\n phosphorylation and the transactivation of some specific regions of their promoters and further underline the preventive rather than curative nature of melatonin regarding\n AD<\/jats:styled-content>\n treatment.\n <\/jats:p>","DOI":"10.1111\/jpi.12200","type":"journal-article","created":{"date-parts":[[2014,12,9]],"date-time":"2014-12-09T12:55:05Z","timestamp":1418129705000},"page":"151-165","source":"Crossref","is-referenced-by-count":84,"title":["Melatonin stimulates the nonamyloidogenic processing of\n \u03b2<\/i>\n APP<\/scp>\n through the positive transcriptional regulation of ADAM10 and ADAM17"],"prefix":"10.1111","volume":"58","author":[{"given":"Mayuri","family":"Shukla","sequence":"first","affiliation":[{"name":"The Research Center for Neuroscience Mahidol University Nakhon Pathom Thailand"},{"name":"Institute of Molecular Biosciences Mahidol University Nakhon Pathom Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Htut Htut","family":"Htoo","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biosciences Mahidol University Nakhon Pathom Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phitchayapak","family":"Wintachai","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biosciences Mahidol University Nakhon Pathom Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean\u2010Francois","family":"Hernandez","sequence":"additional","affiliation":[{"name":"Facult\u00e9 de Pharmacie Institut des Biomol\u00e9cules Max Mousseron UMR5247 CNRS\/Universit\u00e9s Montpellier 1 et 2 Montpellier Cedex 5 France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Dubois","sequence":"additional","affiliation":[{"name":"Immunology Division Department of Pediatrics Universit\u00e9 de Sherbrooke Qu\u00e9bec QC Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf","family":"Postina","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy and Biochemistry Johannes Gutenberg University Mainz Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaxi","family":"Xu","sequence":"additional","affiliation":[{"name":"Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research Institute of Neuroscience College of Medicine Xiamen University Xiamen Fujian China"},{"name":"Degenerative Disease Research Program Sanford\u2010Burnham Medical Research Institute La Jolla CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Checler","sequence":"additional","affiliation":[{"name":"Institut de Pharmacologie Mol\u00e9culaire et Cellulaire CNRS\/Universit\u00e9 de Nice\u2010Sophia\u2010Antipolis Valbonne France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duncan R.","family":"Smith","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biosciences Mahidol University Nakhon Pathom Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piyarat","family":"Govitrapong","sequence":"additional","affiliation":[{"name":"The Research Center for Neuroscience Mahidol University Nakhon Pathom Thailand"},{"name":"Institute of Molecular Biosciences Mahidol University Nakhon Pathom Thailand"},{"name":"Center for Neuroscience and Department of Pharmacology Faculty of Science Mahidol University Bangkok Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Vincent","sequence":"additional","affiliation":[{"name":"The Research Center for Neuroscience Mahidol University Nakhon Pathom Thailand"},{"name":"Institute of Molecular Biosciences Mahidol University Nakhon Pathom Thailand"},{"name":"Centre National de la Recherche Scientifique Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,12,27]]},"reference":[{"key":"e_1_2_7_2_1","first-page":"373","article-title":"The universal nature, unequal distribution and antioxidant function of melatonin and its derivatives","volume":"13","author":"Reiter RJ","year":"2013","journal-title":"Mini\u2010Rev Med 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