Mayuri ShuklaHtut Htut HtooPhitchayapak WintachaiJean Francois HernandezClaire DuboisRolf PostinaHuaxi XuFrédéric CheclerDuncan R. SmithPiyarat GovitrapongBruno VincentMahidol UniversityInstitut des Biomolecules Max MousseronUniversite de SherbrookeJohannes Gutenberg Universitat MainzXiamen UniversitySanford Burnham Prebys Medical Discovery InstituteUniversite Nice Sophia AntipolisCNRS Centre National de la Recherche Scientifique2018-11-232018-11-232015-01-01Journal of Pineal Research. Vol.58, No.2 (2015), 151-1651600079X074230982-s2.0-84922771460https://repository.li.mahidol.ac.th/handle/20.500.14594/35638© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. 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 (AD) display lower melatonin than age-matched controls. Several studies have reported that melatonin can reduce aggregation and toxicity of amyloid-β peptides that are produced from the β-amyloid precursor protein (βAPP). However, whether melatonin can directly regulate the βAPP-cleaving proteases ('secretases') has not been investigated so far. In this study, we establish that melatonin stimulates the α-secretase cleavage of βAPP in cultured neuronal and non-neuronal cells. This effect is fully reversed by ADAM10- and ADAM17-specific inhibitors and requires both plasma membrane-located melatonin receptor activation, and ERK1/2 phosphorylation. Moreover, we demonstrate that melatonin upregulates both ADAM10 and ADAM17 catalytic activities and endogenous protein levels. Importantly, genetic depletion of one or the other protease in mouse embryonic fibroblasts prevents melatonin stimulating constitutive and PKC-regulated sAPPα secretion and ADAM10/ADAM17 catalytic activities. Furthermore, we show that melatonin induces ADAM10 and ADAM17 promoter transactivation, and we identify the targeted promoter regions. Finally, we correlate melatonin-dependent sAPPα production with a protection against staurosporine-induced apoptosis. Altogether, our results provide the first demonstration that melatonin upregulates the nonamyloidogenic ADAM10 and ADAM17 proteases through melatonin receptor activation, ERK phosphorylation and the transactivation of some specific regions of their promoters and further underline the preventive rather than curative nature of melatonin regarding AD treatment.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyArticleSCOPUS10.1111/jpi.12200