Mechanisms of Melatonin in Alleviating Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a chronic, progressive and prevalent neurodegenerative disease characterized by the loss of higher cognitive functions and an associated loss of memory. The thus far "incurable" stigma for AD prevails because of variations in the success rates of different treatment protocols in animal and human studies. Among the classical hypotheses explaining AD pathogenesis, the amyloid hypothesis is currently being targeted for drug development. The underlying concept is to prevent the formation of these neurotoxic peptides which play a central role in AD pathology and trigger a multispectral cascade of neurodegenerative processes post-aggregation. This could possibly be achieved by pharmacological inhibition of β- or γ-secretase or stimulating the nonamyloidogenic α-secretase. Melatonin the pineal hormone is a multifunctioning indoleamine. Production of this amphiphilic molecule diminishes with advancing age and this decrease runs parallel with the progression of AD which itself explains the potential benefits of melatonin in line of development and devastating consequences of the disease progression. Our recent studies have revealed a novel mechanism by which melatonin stimulates the nonamyloidogenic processing and inhibits the amyloidogenic processing of β-amyloid precursor protein (βAPP) by stimulating α -secretases and consequently down regulating both β- and γ-secretases at the transcriptional level. In this review, we discuss and evaluate the neuroprotective functions of melatonin in AD pathogenesis, including its role in the classical hypotheses in cellular and animal models and clinical interventions in AD patients, and suggest that with early detection, melatonin treatment is qualified to be an anti-AD therapy.

Keywords: Alzheimer's disease; aging; amyloid-β peptide; melatonin; neuroprotection.; secretases.

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).

Fig. (2)

Schematic representations of melatonin-dependent regulation of βAPP processing secretases and its possible underlying mechanisms. The proteolytic processing of βAPP by the non-amyloidogenic pathway precludes Aβ formation. Cleavage by α-secretase (ADAM 10) releases sAPPα and C83 which further undergoes cleavage by γ-secretase to generate P3 and AICD fragments; thereby preventing the generation and release of Aβ peptides. In amyloidogenic pathway, βAPP is cleaved by β-secretase (BACE1) releasing sAPPβ and C99 which is subsequently cleaved by γ-secretase to produce Aβ 1-40 and Aβ 1-42 peptides. Stimulation of the melatonin receptors located at the plasma membrane induce ERK phosphorylation probably via three distinct signaling pathways (Gq/PLC/PKC, Gi/PI3K/PDK1/PKC or Gs/cAMP/PKA) thus triggering the activation of transcription factors CREB, Oct-1, and HIF-1 which further increase ADAM10 promoter transactivation and mRNA levels consequently granting more α-secretase activity and sAPPα production fomenting neuroprotection. In the amyloidogenic pathway, melatonin in a receptor-dependent manner attenuates BACE1 and PS1 protein expression and transcriptional levels and decreases levels of C99 which is further cleaved by γ-secretase to generate Aβ peptide. BACE1 promoter region has multiple transcription factor binding sites like for NF-κB. Melatonin inhibits NF-κB activation which could possibly regulate melatonin induced decrease in BACE1 and C99 expression. Thus melatonin-dependent transcriptional activation of α-secretases and down regulation of BACE1 and PSI levels strongly indicates the beneficial role of melatonin in AD pathology thereby precluding Aβ production. Aβ, beta-amyloid; ADAM10, α-secretase; BACE1, β-secretase; Mel, melatonin; MT1/2, melatonin receptor; NF-κB, nuclear factor- kappa light-chain enhancer of activated B cells; PS1, presenilin1; PKA, Protein kinase A; MEK1, mitogen-activated protein kinase kinase 1; AICD, The amyloid precursor protein intracellular domain.