Melatonin Mechanisms in Alzheimer's Disease Pathology

Melatonin, a pineal hormone regulating circadian rhythms, has emerged as a multifaceted modulator of Alzheimer’s disease (AD) pathology. Beyond its chronobiotic role, melatonin exerts potent antioxidant and anti-inflammatory actions that protect neurons from the oxidative stress and neuroinflammation inherent to AD. It interacts directly with amyloid-beta species to inhibit fibril formation and attenuates tau hyperphosphorylation by modulating kinase and phosphatase activities. Melatonin preserves mitochondrial integrity by enhancing respiratory efficiency, promoting mitophagy and stabilising mitochondrial dynamics. Dysfunction of the melatonergic system in ageing and AD—manifested by reduced nocturnal secretion and disrupted receptor signalling—correlates with accelerated amyloid and tau pathology, synaptic loss and cognitive decline. Preclinical data support melatonin’s capacity to ameliorate synaptic dysfunction, reduce plaque burden and improve spatial memory, suggesting its potential as both a biomarker of disease progression and a therapeutic agent. Optimising dosage, delivery and timing remains imperative to translate these mechanisms into clinical benefit.

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Melatonin Mechanisms in Alzheimer's Disease Pathology publication trend

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Technical terms

Melatonin: Endogenous indoleamine hormone secreted by the pineal gland that regulates sleep-wake cycles and exerts antioxidant and anti-inflammatory effects.

Amyloid-beta: Peptide derived from amyloid precursor protein that aggregates into extracellular plaques, a hallmark of Alzheimer’s pathology.

Tau phosphorylation: Post-translational modification of the microtubule-associated protein tau, leading to neurofibrillary tangles when hyperphosphorylated.

Circadian rhythm: Endogenous, approximately 24-hour physiological cycle governing behavioural and metabolic processes.

Oxidative stress: Imbalance between reactive oxygen species production and antioxidant defences, causing cellular damage.

Autophagy: Intracellular degradation pathway for recycling damaged organelles and protein aggregates, essential for neuronal homeostasis.

References

1. Melatonin: A potential nighttime guardian against Alzheimer’s. Molecular Psychiatry (2024).
2. Oxidative Stress and Aging as Risk Factors for Alzheimer’s Disease and Parkinson’s Disease: The Role of the Antioxidant Melatonin. International Journal of Molecular Sciences (2023).
3. Prophylactic melatonin significantly reduces Alzheimer’s neuropathology and associated cognitive deficits independent of antioxidant pathways in AβPPswe/PS1 mice. Molecular Neurodegeneration (2015).