Therapeutic potential of melatonin-induced mitophagy in the pathogenesis of Alzheimer's disease

Abstract

Neurons rely heavily on functional mitochondria for energy production. Mitochondrial dysfunction is a key player in age-related neurodegenerative diseases like Alzheimer's disease (AD). In AD, damaged mitochondria accumulate early, worsening the disease. This dysfunction disrupts cellular balance in neurons, leading to energy deficiencies, calcium imbalances, and oxidative stress. These issues further aggravate the harmful effects of amyloid beta (Aβ) plaques and tau tangles, ultimately leading to synaptic dysfunction, memory loss, and cognitive decline. While a complex link exists between mitochondrial dysfunction and AD hallmarks like Aβ plaques and tau tangles, the exact cause-and-effect relationship remains unclear. Additionally, recent evidence suggests impaired mechanisms for mitophagy in AD. Mitophagy is crucial for neuronal health, and studies have found changes to proteins involved in this process, mitochondrial dynamics, and mitochondrial production in AD. Impaired mitophagy might also be linked to problems with how cells fuse waste disposal compartments (autophagosomes) with lysosomes, and issues with maintaining proper acidity within lysosomes. Interestingly, melatonin, a hormone known for regulating sleep, has recently emerged as a potential neuroprotective agent. Studies using a mouse model of AD showed that melatonin treatment improved cognitive function by enhancing mitophagy. These findings suggest that melatonin's ability to improve mitophagy may be a promising avenue for future AD therapies. Therefore, in this review, we discuss the therapeutic effect of melatonin on mitochondrial dysfunction, especially mitophagy, in AD.

Keywords: Alzheimer’s disease; Amyloid-beta; Melatonin; Mitochondrial dysfunction; Mitophagy; Oxidative stress; Tau pathology.