title: Melatonin stimulates the nonamyloidogenic processing of βAPP through the positive transcriptional regulation of ADAM10 and ADAM17.
abstract: 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.
authors.affiliation: The Research Center for Neuroscience, Mahidol University, Nakhon Pathom, Thailand; Institute of Molecular Biosciences, Mahidol University, Nakhon Pathom, Thailand.
authors.forename: Mayuri
authors.initials: M
authors.lastname: Shukla
authors.forename: Htut Htut
authors.initials: HH
authors.lastname: Htoo
authors.forename: Phitchayapak
authors.initials: P
authors.lastname: Wintachai
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Hernandez
authors.forename: Claire
authors.initials: C
authors.lastname: Dubois
authors.forename: Rolf
authors.initials: R
authors.lastname: Postina
authors.forename: Huaxi
authors.initials: H
authors.lastname: Xu
authors.forename: Frédéric
authors.initials: F
authors.lastname: Checler
authors.forename: Duncan R
authors.initials: DR
authors.lastname: Smith
authors.forename: Piyarat
authors.initials: P
authors.lastname: Govitrapong
authors.forename: Bruno
authors.initials: B
authors.lastname: Vincent
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D008550:Melatonin / Q000494:pharmacology*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse; D008550:Melatonin
keywords: Alzheimer; apoptosis; melatonin; metabolism; secretase; transcription