Potential Role of Extrapineal Melatonin as a Neurohormone in the Pathophysiology of Alzheimer’s Disease: Unanswered Questions

Melatonin, the pineal gland hormone, is produced in various extrapineal tissues as well, and its reduction has been reported in sporadic Alzheimer's disease (AD). The exact reason for tissue melatonin synthesis, despite the pineal source of melatonin, is not well understood, although the melatonin decline in the biological fluids of AD patients is a reasonable justification for melatonin therapy in cognitive impairment. However, the effectiveness of melatonin administration in AD patients was insignificant. Additionally, there is evidence of alterations in local melatonin synthesis in pathological situations, and little is known regarding its physiological or pathological modulators. Recently, the decline in the hippocampal enzyme of melatonin synthesis has been reported in amyloid-β neurotoxicity. It has been shown that reduced hippocampal melatonin synthesis by siRNA has been associated with cognitive decline. This review has included AD studies that noticed the impacts of melatonin prescription on memory and cognitive function in both animal research and randomized controlled trials, while also reviewing the available data regarding the alterations in brain tissue melatonin synthesis. This review highlights the role of brain (extrapineal) tissue melatonin synthesis in cognitive function in AD pathophysiology. Understanding the induction pattern of extrapineal melatonin synthesis, dosing optimization of exogenous administration, noting gender-specific differences, and clarifying microbiota-melatonin interactions point toward new approaches that may enhance the effectiveness of melatonin-based interventions for preventing or delaying AD progression.