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Melatonin stimulates the nonamyloidogenic processing of β APP through the positive transcriptional regulation of ADAM10 and ADAM17
Author(s) -
Shukla Mayuri,
Htoo Htut Htut,
Wintachai Phitchayapak,
Hernandez JeanFrancois,
Dubois Claire,
Postina Rolf,
Xu Huaxi,
Checler Frédéric,
Smith Duncan R.,
Govitrapong Piyarat,
Vincent Bruno
Publication year - 2015
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/jpi.12200
Subject(s) - melatonin , adam10 , proteases , transactivation , biology , alpha secretase , microbiology and biotechnology , neuroprotection , amyloid precursor protein , receptor , pinealocyte , endocrinology , medicine , melatonin receptor , alzheimer's disease , pineal gland , disintegrin , matrix metalloproteinase , biochemistry , pharmacology , metalloproteinase , gene expression , disease , gene , enzyme
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 ( β APP ). However, whether melatonin can directly regulate the β APP ‐cleaving proteases (‘secretases’) has not been investigated so far. In this study, we establish that melatonin stimulates the α‐secretase cleavage of β APP in cultured neuronal and non‐neuronal cells. This effect is fully reversed by ADAM 10‐ and ADAM 17‐specific inhibitors and requires both plasma membrane‐located melatonin receptor activation, and ERK 1/2 phosphorylation. Moreover, we demonstrate that melatonin upregulates both ADAM 10 and ADAM 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 PKC ‐regulated sAPP α secretion and ADAM 10/ ADAM 17 catalytic activities. Furthermore, we show that melatonin induces ADAM 10 and ADAM 17 promoter transactivation, and we identify the targeted promoter regions. Finally, we correlate melatonin‐dependent sAPP α production with a protection against staurosporine‐induced apoptosis. Altogether, our results provide the first demonstration that melatonin upregulates the nonamyloidogenic ADAM 10 and ADAM 17 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.