Melatonin regulates the aging mouse hippocampal homeostasis via the sirtuin1-FOXO1 pathway
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Date
2017-03-23
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Abstract
Sirtuin1 (SIRT1) and forkhead box transcription factor O subfamily 1 (FOXO1) play vital roles in
the maintenance of hippocampal neuronal homeostasis during aging. Our previous study showed that
melatonin, a hormone mainly secreted by the pineal gland, restored the impaired memory of aged
mice. Age-related neuronal energy deficits contribute to the pathogenesis of several
neurodegenerative disorders. An attempt has been made to determine whether the effect of melatonin
is mediated through the SIRT1-FOXO1 pathways. The present results showed that aged mice (22 months
old) exhibited significantly downregulated SIRT1, FOXO1, and melatonin receptors MT1 and MT2
protein expression but upregulated tumor suppressor protein 53 (p53), acetyl-p53 protein (Ac-p53),
mouse double minute 2 homolog (MDM2), Dickkopf-1 (DKK1) protein expression in mouse hippocampus
com- pared with the young group. Melatonin treatment (10 mg/kg, daily in drinking water for 6
months) in aged mice significantly attenuated the age-induced downregulation of SIRT1, FOXO1, MT1
and MT2 protein expression and attenuated the age-induced increase in p53, ac-p53, MDM2, and DKK1
protein and mRNA expression. Mel- atonin decreased p53 and MDM2 expression, which led to a decrease
in FOXO1 degradation. These present results suggest that melatonin may help the hippocampal
neuronal homeostasis by increasing SIRT1, FOXO1 and mela- tonin receptors expression while
decreasing DKK1 expression in the aging hippocampus. DKK1 can be induced by the accumulation of amyloid β (Aβ) which is the major hallmark of Alzheimer’s disease.
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Keywords
melatonin, aging, hippocampus, sirtuin1, FOXO1, melatonin receptor