The Effects of Melatonin on Cognition and Αβ load in an Alzheimer’s Disease Mouse Model

Abstract

AbstractBackgroundThe neurohormone melatonin is released from the pineal gland and is an endogenous antioxidant and free radical scavenger that regulates sleep/wake cycle and circadian rhythm. Decline of nocturnal melatonin secretion with severe sleep disturbance has been consistently reported in Alzheimer’s Disease (AD), a neurodegenerative disease characterized by cognitive deficits and neuronal loss. However, exogenous melatonin supplementation can reduce Αβ neurotoxicity and formation while improving cognitive performance and sleep quality.MethodIn this study, the long‐term influence of melatonin on behavioral and neuropathological changes were evaluated in the 5xFAD mouse model, when treatment was started in adolescence. After ∼20 weeks of orally administered melatonin (10 mg/kg), Morris water maze behaviour was assessed in 54 mice, followed by Aβ42 quantification in hippocampal tissue.ResultOverall, transgenic mice showed impaired learning, and a significant increase in Aβ42 plaque load, replicating previous results with this strain. Melatonin marginally improved learning by decreasing distance travelled in the Morris water maze and slightly decreasing Aβ42 concentration in the hippocampus. These results support the hypothesis that long‐term melatonin supplementation may be beneficial at early stages of the disease process and should be explored more fully.ConclusionAbnormal accumulation of neurotoxic forms of Αβ occur in brain regions involved in the regulation of sleep in AD patients and the disturbed regulation of sleep that occurs early in the disease may contribute to cognitive decline by decreasing Αβ clearance. In contrast to conventional antioxidants, melatonin crosses the blood‐brain barrier, is relatively devoid of toxicity, and constitutes a straight‐forward potential therapeutic candidate in AD treatment.