title: Melatonin regulates the transcription of βAPP-cleaving secretases mediated through melatonin receptors in human neuroblastoma SH-SY5Y cells.
abstract: Melatonin is involved in the control of various physiological functions, such as sleep, cell growth and free radical scavenging. The ability of melatonin to behave as an antioxidant, together with the fact that the Alzheimer-related amyloid β-peptide (Aβ) triggers oxidative stress through hydroxyl radical-induced cell death, suggests that melatonin could reduce Alzheimer's pathology. Although the exact etiology of Alzheimer's disease (AD) remains to be established, excess Aβ is believed to be the primary contributor to the dysfunction and degeneration of neurons that occurs in AD. Aβ peptides are produced via the sequential cleavage of β-secretase β-site APP-cleaving enzyme 1 (BACE1) and γ-secretase (PS1/PS2), while α-secretase (ADAM10) prevents the production of Aβ peptides. We hypothesized that melatonin could inhibit BACE1 and PS1/PS2 and enhance ADAM10 expression. Using the human neuronal SH-SY5Y cell line, we found that melatonin inhibited BACE1 and PS1 and activated ADAM10 mRNA level and protein expression in a concentration-dependent manner and mediated via melatonin G protein-coupled receptors. Melatonin inhibits BACE1 and PS1 protein expressions through the attenuation of nuclear factor-κB phosphorylation (pNF-κB). Moreover, melatonin reduced BACE1 promoter transactivation and consequently downregulated β-secretase catalytic activity. The present data show that melatonin is not only a potential regulator of β/γ-secretase but also an activator of α-secretase expression through the activation of protein kinase C, thereby favoring the nonamyloidogenic pathway over the amyloidogenic pathway. Altogether, our findings suggest that melatonin may be a potential therapeutic agent for reducing the risk of AD in humans.
authors.affiliation: Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Nakhonpathom, Thailand.
authors.forename: Jiraporn
authors.initials: J
authors.lastname: Panmanee
authors.affiliation: Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Nakhonpathom, Thailand.
authors.forename: Chutikorn
authors.initials: C
authors.lastname: Nopparat
authors.affiliation: Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Nakhonpathom, Thailand.
authors.forename: Napapit
authors.initials: N
authors.lastname: Chavanich
authors.affiliation: Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Nakhonpathom, Thailand.
authors.forename: Mayuri
authors.initials: M
authors.lastname: Shukla
authors.affiliation: Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Nakhonpathom, Thailand.
authors.forename: Sujira
authors.initials: S
authors.lastname: Mukda
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, Faculty of Medicine, The University of British Columbia, Vancouver, BC, Canada.
authors.forename: Weihong
authors.initials: W
authors.lastname: Song
authors.affiliation: Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Nakhonpathom, Thailand.|Centre National de la Recherche Scientifique, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Vincent
authors.affiliation: Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Nakhonpathom, Thailand.|Center for Neuroscience and Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors.forename: Piyarat
authors.initials: P
authors.lastname: Govitrapong
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008550:Melatonin / Q000494:pharmacology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism*; D053763:Presenilins / Q000235:genetics / Q000378:metabolism; D044094:Receptors, Melatonin / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; D053763:Presenilins; D044094:Receptors, Melatonin; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D008550:Melatonin
keywords: Alzheimer's disease; a disintegrin and metalloproteinase 10; melatonin; presenilin; secretase; β-amyloid precursor protein; β-site APP-cleaving enzyme 1