Exploring the multifunctional role of melatonin in regulating autophagy and sleep to mitigate Alzheimer’s disease neuropathology

Melatonin (MLT) is a neurohormone that is regulated by the circadian clock and plays multifunctional roles in numerous neurodegenerative disorders, such as Alzheimer's disease (AD). Alzheimer's disease is the most common form of dementia and is associated with the degradation of axons and synapses resulting in memory loss and cognitive impairment. Despite extensive research, there is still no effective cure or specific treatment to prevent the progression of AD. The pathogenesis of AD involves atrophic alterations in the brain that also result in circadian alterations, sleep disruption, and autophagic dysfunction. In this scenario, MLT and autophagy play a central role in removing the misfolded protein aggregations. Melatonin also promotes autophagy through inhibiting methamphetamine toxicity to protect against neuronal cell death in AD brain. Besides, MLT plays critical roles as either a pro-autophagic indicator or anti-autophagic regulator depending on the phase of autophagy. Melatonin also has antioxidant properties that can counteract mitochondrial damage, oxidative stress, and apoptosis. Aging, a major risk factor for AD, can change sleep patterns and sleep quality, and MLT can improve sleep quality through regulating sleep cycles. The primary purpose of this review is to explore the putative mechanisms of the beneficial effects of MLT in AD patients. Furthermore, we also summarize the findings from preclinical and clinical studies on the multifunctional roles of MLT on autophagic regulation, the control of the circadian clock-associated genes, and sleep regulation.