title: Melatonin administration reverses the alteration of amyloid precursor protein-cleaving secretases expression in aged mouse hippocampus.
abstract: Beta-amyloid (Aβ) peptide is the pathological hallmark of Alzheimer's disease (AD). Interestingly, Aβ is normally synthesized in the brain of healthy people; however, during advanced aging, the level of Aβ peptides increases. As a result, the aggregation of Aβ peptides leads to trafficking problems, synaptic loss, inflammation, and cell death. Melatonin, the hormone primarily synthesized and secreted from the pineal gland, is decreased with progressing age, particularly in Alzheimer's disease patients. The loss of melatonin levels and the abnormal accumulation of some proteins, such as Aβ peptides in the brains of AD patients are considered important factors in the initiation of the cognitive symptoms of dementia. A previous study in mice reported that increased brain melatonin levels remarkably diminished the potentially toxic Aβ peptide levels. The present study showed that aged mice significantly impaired spatial memory in the Morris Water Maze task. We also showed that α-, β-, and γ-secretases, which are type-I membrane protein proteases responsible for Aβ production, showed alterations in both mRNA and protein expression in the hippocampus of aged mice. The long-term administration of melatonin, mice had shorter escape latencies and remained in the target quadrant longer compared to the aged group. Melatonin attenuated the reduction of α-secretase and inhibited the increase of β- and γ-secretases. Moreover, melatonin attenuated the upregulation of pNFkB and the reduction of sirtuin1 in the hippocampus of aged mice. These results suggested that melatonin protected against Aβ peptide production in aged mice. Hence, melatonin loss in aging could be recompensed through dietary supplementation as a beneficial therapeutic strategy for AD prevention and progression.
authors.affiliation: Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhon Pathom 73170, Thailand.
authors.forename: Sujira
authors.initials: S
authors.lastname: Mukda
authors.affiliation: Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhon Pathom 73170, Thailand.
authors.forename: Jiraporn
authors.initials: J
authors.lastname: Panmanee
authors.affiliation: Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhon Pathom 73170, Thailand.
authors.forename: Parichart
authors.initials: P
authors.lastname: Boontem
authors.affiliation: Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhon Pathom 73170, Thailand; Center for Neuroscience and Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand. Electronic address: piyarat.gov@mahidol.ac.th.
authors.forename: Piyarat
authors.initials: P
authors.lastname: Govitrapong
mesh_terms: D000072197:ADAM10 Protein / Q000378:metabolism; D000375:Aging / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D018782:Maze Learning; D008550:Melatonin / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D016328:NF-kappa B; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D008550:Melatonin
keywords: Aging; Alzheimer’s disease; Beta-amyloid; Hippocampus; Melatonin; Secretases