Melatonin administration reverses the alteration of amyloid precursor protein-cleaving secretases expression in aged mouse hippocampus

Beta-amyloid (A beta) peptide is the pathological hallmark of Alzheimer's disease (AD). Interestingly, A beta is normally synthesized in the brain of healthy people; however, during advanced aging, the level of A beta peptides increases. As a result, the aggregation of Ail 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 A beta 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 A beta peptide levels. The present study showed that aged mice significantly impaired spatial memory in the Morris Water Maze task. We also showed that alpha-, beta-, and gamma-secretases, which are type-I membrane protein proteases responsible for A beta 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 alpha-secretase and inhibited the increase of beta- and gamma-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 A beta 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. (C) 2016 Elsevier Ireland Ltd. All rights reserved.