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. 2017 Oct;15(7):1010–1031. doi: 10.2174/1570159X15666170313123454

Fig. (1).

Fig. (1)

Comprehensive summarization of melatonin therapy in different classical hypotheses of AD pathogenesis. This figure summarizes the potential therapeutic targets of melatonin in AD treatment. Melatonin is metabolized into its kynuramine derivatives AFMK (N1-acetyl-N2-formyl-5-methoxykynuramine), AMK (N1-acetyl-5-methoxykynuramine) and 3-OHM (cyclic 3-hydroxymelatonin) which also possess neuroprotective biological and pharmacological properties. Melatonin levels strongly decrease with advancing age and patients with AD exhibit lower melatonin levels than age matched controls. In this context, melatonin via its action on the circadian oscillators modulate and synchronize the rhythms, regulates the epigenetic processes and stimulates the anti-oxidant defense system in the brain thereby improving cognition and sleep disorders. Melatonin also promotes neuronal survival by stimulating neurogenesis. Among the classical hypotheses of AD, melatonin has a protective effect on the cholinergic system by stimulating both choline transport and ChAT activity and down regulating AchE activity. By regulating the important kinases (GSK3β, cdk5) melatonin attenuates hyperphosphorylation of tau thereby precluding tangle formation. Melatonin stimulates the non-amyloidogenic and down regulates the amyloidogenic processing of βAPP thereby precluding the formation of Aβ peptides. Aβ-induced microglial activation is an important factor in AD pathogenesis and in this frame of reference melatonin attenuates proinflammatory cytokines, inhibits NFκB activity and reduces oxidative damage. Melatonin regulates blood glucose circadian rhythm by stimulating IGF-1 activity and modulating insulin resistance. Melatonin regulates Aβ-induced altered calcium and mitochondrial homeostasis thus protecting cells against oxidative stress and cell death and also regulates cholesterol homeostasis further preventing peroxidation of neuronal membrane lipids. Therefore, the diverse biological and physiological properties of melatonin employ it to be a neuroprotective drug in the treatment of AD. (↑ = stimulation, ⊥ = inhibition).