Melatonin ameliorates amyloid beta-induced memory deficits, tau hyperphosphorylation and neurodegeneration via PI3/Akt/GSk3 pathway in the mouse hippocampus

Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disease, pathologically characterized by the accumulation of amyloid beta (A) aggregation in the brain, and is considered to be the primary cause of cognitive dysfunction. A aggregates lead to synaptic disorder, tau hyperphosphorylation, and neurodegeneration. In this study, the underlying neuroprotective mechanism of melatonin against A(1-42)-induced neurotoxicity was investigated in the mice hippocampus. Intracerebroventricular (i.c.v.) A(1-42)-injection triggered memory impairment, synaptic disorder, hyperphosphorylation of tau protein, and neurodegeneration in the mice hippocampus. After 24hr of A(1-42) injection, the mice were treated with melatonin (10mg/kg, intraperitonially) for 3wks, reversed the A(1-42)-induced synaptic disorder via increasing the level of presyanptic (Synaptophysin and SNAP-25) and postsynaptic protein [PSD95, p-GluR1 (Ser845), SNAP23, and p-CREB (Ser133)], respectively, and attenuated the A(1-42)-induced memory impairment. Chronic melatonin treatment attenuated the hyperphosphorylation of tau protein via PI3K/Akt/GSK3 signaling by activating the p-PI3K, p-Akt (Ser 473) and p-GSK3 (Ser9) in the A(1-42)-treated mice. Furthermore, melatonin decreased A(1-42)-induced apoptosis through decreasing the overexpression of caspase-9, caspase-3, and PARP-1 level. Additionally, the evaluation of immunohistochemical analysis of caspase-3, Fluorojade-B, and Nissl staining indicated that melatonin prevented neurodegeneration in A(1-42)-treated mice. Our results demonstrated that melatonin has neuroprotective effect against A(1-42)-induced neurotoxicity through decreasing memory impairment, synaptic disorder, tau hyperphosphorylation, and neurodegeneration via PI3K/Akt/GSK3 signaling in the A(1-42)-treated mouse model of AD. On the basis of these results, we suggest that melatonin could be an effective, promising, and safe neuroprotective candidate for the treatment of progressive neurodegenerative disorders, such as AD.