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Study links long-term melatonin use to heart problems November 2025
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Chronobiology and Neurodegeneration: The Role of Melatonin in Alzheimer's Disease
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Open access
Introduction
Alzheimer’s disease (AD) is a severe life threatening, chronic age-related neurodegenerative disease (Lin et al., 2013) and a leading cause of dementia affecting more than 55 million people on a global basis (Gale et al., 2018). Pathological hallmarks of AD are characterized by the formation and accumulation of extracellular senile plaques (SPs) composed of β-amyloid (Aβ) and neurofibrillary tangles (NFTs) present intracellularly, which are made up of abnormal hyperphosphorylated tau, a protein of microtubule family (Scheltens et al., 2021). Despite the tremendous amounts of research, the etiology of AD alongside it’s molecular players have not yet been fully discovered. However, studies have pointed at a few known mechanisms that contribute to AD pathophysiology, that includes genetic predisposition (for e.g. expression levels of Apolipoproteins (APOE4) and presenilins (PS) genes like PSEN1 and PSEN2), inflammation, oxidative stress, mitochondrial dysfunction, neurotoxicity by neurotoxicants and environmental factors (Lane et al., 2018).
Table 1. Summary Table highlighting the effect of melatonin on each of the pathophysiological outcome of AD
| Sr. No | Pathophysiology | Effect of Melatonin | Mechanisms | Limitations |
|---|---|---|---|---|
| 1 | Aβ neurotoxicity & production/clearance balance | Lowers brain oligomeric Aβ, shifts Aβ toward soluble/peripheral pools, reduces Aβ-induced toxicity (preclinical). | Inhibits β/γ-secretase activity, promotes clearance, reduces oxidative stress and aggregation. | Mostly animal data with supraphysiological doses; indirect clearance measures; unclear preventive vs therapeutic timing. |
| 2 | Mechanisms of melatonin-mediated neuroprotection against Aβ | Reduces synaptic loss and cell death, preserves cognition in Aβ-exposed models. | Antioxidant, anti-apoptotic, inhibition of Aβ oligomerization, MT1/MT2 and SIRT1 pathways. | Pleiotropic actions obscure primary mechanism; limited causal blockade experiments. |
| 3 | Tau pathology | Decreases tau hyperphosphorylation and aggregation in vitro and in vivo. | Modulates kinases (↓GSK3β, ↓CDK5) and phosphatases; reduces oxidative stress. | Limited chronic models; unclear receptor dependence; few human data. |
| 4 | Circadian–metabolic bridge: melatonin & insulin | Improves insulin signaling, rescues hippocampal insulin resistance in metabolic and STZ models. | Enhances IRS/Akt phosphorylation, reduces inflammation and oxidative stress; aligns metabolic rhythms. | Species differences; pharmacologic doses; unclear central vs peripheral effects. |
| 5 | Oxidative stress | Reduces ROS, lipid peroxidation and oxidative damage markers across models. | Free-radical scavenging; upregulates Nrf2 and antioxidant enzymes; stabilizes mitochondria. | High doses used; difficulty separating direct from secondary effects. |
| 6 | Chronoprotective role (circadian regulation) | Restores sleep–wake cycles and clock gene expression; improves sleep quality. | Activates MT1/MT2 receptors, phase-shifts clock, synchronizes peripheral/central rhythms. | Heterogeneous dosing/timing; species differences; reduced efficacy in advanced disease. |
| 7 | BBB stability | Preserves tight junction proteins, reduces BBB permeability and MMP activity. | Anti-inflammatory (↓NF-κB/TLR4), MMP-9 inhibition, antioxidant protection, AMPK activation. | Acute models dominate; chronic AD-related BBB dysfunction underexplored. |
| 8 | Mitochondrial protection | Improves mitochondrial respiration, reduces ROS, prevents mPTP opening. | Activates SIRT1/PGC-1α, stabilizes membrane potential, inhibits cytochrome c release. | In vivo mitochondrial data limited; unclear direct vs secondary effects. |
| 9 | Neuroinflammation | Attenuates microglial/astrocytic activation and lowers pro-inflammatory cytokines. | Suppresses NF-κB/TLR4 signaling, decreases iNOS/COX2, promotes anti-inflammatory phenotype. | Acute LPS/toxin models; limited translational biomarkers or human data. |
| 10 | Cholinergic hypothesis | Restores ACh levels, reduces AChE activity, protects cholinergic neurons. | Reduces oxidative stress, preserves choline acetyltransferase, indirect anti-inflammatory effects. | Sparse mechanistic data; inconsistent cognitive effects clinically. |
| 11 | Calcium hypothesis | Stabilizes intracellular Ca2+, reduces Ca2+-mediated toxicity in neurons. | Modulates NMDA receptor activity, supports mitochondrial Ca2+ buffering. | Mostly in vitro data; chronic Ca2+ dysregulation in AD not fully modeled. |
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Figure 13Melatonin (N-acetyl-5-methoxytryptamine), a key hormone produced by pineal gland is a tryptophan metabolite, which exerts its role in a varied range of physiological functions such as regulation of the circadian rhythms, maintaining sleep-wake cycle, managing oxidative stress levels, immunological aspects and clearance of free radicals(Prodhan et al., 2021). The production of melatonin, is done through a series of enzymatic reactions in pineal gland that involves other metabolites such as serotonin, N-acetyl serotonin and 5-hydroxytryptophan. Melatonin, an endocrine hormone with amphiphilic properties are secreted directly into the bloodstream at night by pineal gland, thereby affecting both central nervous system(CNS) and peripheral nervous system(PNS) organs(Claustrat & Leston, 2015). Human research studies have shown that pineal gland can also release melatonin directly into brain ventricles (Leston et al., 2010). From the bloodstream, melatonin is directly taken up by the liver, where it is converted to 6-hydroxymelatonin sulfate, via a series of enzymatic reactions, and lastly excreted through urine (Bojkowski et al., 1987).
Melatonin primarily influences the target cells by binding to two of the G-protein coupled receptors namely melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2) (de Lima Menezes et al., 2024). Melatonin receptor 3 (MT3) is involved in events that exercises protection due to oxidative stress (de Lima Menezes et al., 2024). The localisation of MT1 and MT2 is not homogenous. MT1 is found in various organs and tissues such as superior chiasmatic nucleus (SCN), ovary, cerebellum, testis, kidney, liver etc. whereas MT2 is more restricted towards brain and partly found in liver and heart tissues (Dubocovich & Markowska, 2005). Activation of MT1 and MT2 receptors lead to the initiation of various signalling pathways, one of which includes the inhibition of adenylate cyclase, which produces cyclone adenosine monophosphate (cAMP), a secondary messenger crucial for cellular and physiological processes (Ahmad et al., 2023). Moreover, melatonin extends its biological activities such as interaction with nuclear receptors and membrane bound intracellular proteins such as calmodulin (Cecon et al., 2018).
Role of Melatonin in Alzheimer’s Disease
Apart from regulating the sleep-wake cycles, and maintain the circadian rhythms melatonin implicates direct and indirect association with pathways involved in AD pathophysiology (Arendt & Skene, 2005). This includes the potential of melatonin to reduce the production of Aβ plaques, alongside exercising it’s protective effect on the Aβ oligomers, which are the most deadly and pathogenic form of Aβ. Melatonin also have been partially found to be involved in modulation of hyperphosphosphorylation of tau (Cline et al., 2018a). Moreoever, melatonin exerts it’s neuroprotective effect by reducing the oxidative stress levels, and promoting the clearance of free radicals in the CNS (D. Xu et al., 2020). Additionally melatonin implicates its effects on circadian processes of brain cells, organizes neural activity, modulates synaptic transmission activity in regard to natural sleep wake cycle, which could potentially alleviate the pathological symptoms of AD (Kruk et al., 2021). Melatonin may influence AD pathology through several additional protective mechanisms, including improved blood-brain barrier (BBB) function, increased removal of metabolites and protein fragments associated with AD; a process largely driven by astrocytes during sleep and enhanced insulin signalling, which is also thought to contribute to AD (De Felice et al., 2022a).
The production of melatonin decreases as the human brain ages, due to the age-related calcification process of pineal gland rather than it’s increased clearance ability (Sack et al., 1986). Clinically speaking, reduced melatonin levels, and disturbed 24-hour melatonin rhythmic cycles are common symptoms observed in patients with dementia and AD (J. L. Wang et al., 2015). Decreased melatonin levels in serum and cerebrospinal fluid (CSF), and disturbed melatonin diurnal rhythm are observed in AD patients (J.-N. Zhou et al., 2003a). Moreoever, CSF melatonin levels decreases significantly as AD progresses pathologically, whose severity is determined by braak stages (R. Y. Liu et al., 1999a). Reduced melatonin levels, are also a key characteristic of preclinical subjects of AD, who are intact cognitively but show early signs of AD thereby regarding it as an important biomarker for the identification of early-onset alzheimer’s disease(EOAD) (Y.-H. Wu et al., 2003). Although molecular alterations occur in the pineal gland of AD patients, there are no observed differences in pineal gland’s weight, degree of calcification, or overall protein content (Friedland et al., 1990). It has also been found that β1-adrenergic receptor mRNA is absent and both the activity and gene expression of monoamine oxidase (MAO) are increased in AD patients. This indicates that disrupted noradrenergic signalling and decreased serotonin, the precursor to melatonin, which might be the cause of melatonin rhythm loss and decreased melatonin levels observed in AD (Y.-H. Wu et al., 2007). External melatonin supplementation, has been suggested as a treatment option for AD patients, which mitigates the effects of agitated behaviour, confusion and “sundowning” symptoms and improves cognitive functioning of AD patients (Cardinali et al., 2002). Thus, this makes melatonin supplementation, which is very less toxic and hideous towards normal functioning of AD patients, a possible symptomatic treatment option.
Since melatonin can alleviate certain clinical symptoms of AD and its levels significantly decline during the progression of the condition, exploring the connection between melatonin and AD pathology may offer valuable insights into its potential for prevention or treatment. This review will focus on melatonin's role in Aβ toxicity, tau hyperphosphorylation, mitochondrial dysfunction, oxidative stress, calcium imbalance, cholinergic system dysregulation, neuroinflammatory microglial activity responses, BBB, insulin resistance and role in regulating circadian rhythms. Each section will cover observations, evidence, mechanism, and theoretical interpretations in a structure pattern.
Melatonin and its potential roles in Aβ neurotoxicity and production/clearance balance
Cleavage of amyloid precursor protein (APP) by β- and γ-secretases leads to the production of Aβ. The production of Aβ fragments follows two classical pathways in AD pathogenesis: amyloidogenic and non-amyloidogenic pathway(Ma et al., 2022). Amyloidogenic processing pathway is initiated when the APP is cleaved by β-secretases in order to form a C-terminal fragment (CTF) with 99 amino acids (C99). C99 is later cleaved by γ-secretases to produce pathogenic forms of Aβ. This amyloidogenic pathway produces neurotoxic fragments like Aβ1− 40 and Aβ1− 42 (Armstrong, 2013). Majority of APP undergoes the non-amyloidogenic pathway first, in which APP is cleaved by α-secretases, which further forms a N- terminal soluble APP- α and C-terminal fragment of 83 amino acids knows as C83. Further C83 is cleaved by γ-secretases to release APP intracellular domain (AICD) (Bruno et al., 2021). Increased levels of non-amyloidogenic pathway processing leads to reduction in production of Aβ and ameliorates the effects mediated by AD pathology (Rostagno, 2022).
A. Evidence
Increased production of Aβ and impaired clearance of Aβ, leads to the assembly and accumulation of Aβ, later on which leads to formation of toxic forms of Aβ, called as oligomeric Aβ and amyloid fibrils. Hence inhibition of this Aβ fibril formation and accumulation is another intervention to stop AD pathogenesis(Rostagno, 2022). Various research studies have shown that melatonin has the ability to slow down or diminish the Aβ production and improper accumulation, by enhancing the non-amyloidogenic APP processing pathway (Minich et al., 2022). Additionally when not comparing with previous conventional models of Aβ plaque formation, melatonin interacts with several biological pathways. For instance, melatonin has been shown to promote α-secretase cleavage of βAPP in both neuronal and non-neuronal cultured cells by increasing the expression of the non-amyloidogenic proteases ADAM10 and ADAM17. Conversely, when α-secretase inhibitors are present in these cell lines, melatonin's ability to activate the non-amyloidogenic pathway through α-secretase is blocked(Shukla et al., 2015). Research using SH-SY5Y cells, a well-established model for investigating neurodegeneration, has shown that melatonin suppresses the expression of amyloidogenic β-secretases(Panmanee et al., 2015). Melatonin treatment appears to reduce the levels of Aβ in the brains of both sporadic and transgenic animal models of AD(Ng et al., 2010). This effect may be due to its ability to simultaneously enhance α-secretase activity, an enzyme that promotes non-amyloidogenic processing of amyloid precursor protein and reduce β-secretase activity, which is involved in Aβ generation. Interestingly, this interaction seems to be bi-directional: studies have shown that Aβ peptides can significantly suppress melatonin production by the pineal gland(Cecon et al., 2015), suggesting a feedback loop that may further influence disease progression.
B. Mechanism
Melatonin appears to regulate the activity of enzymes involved in the processing of membrane-bound APP) in neurons, notably glycogen synthase kinase-3β (GSK3β) (Uemura et al., 2007). GSK3β, a serine/threonine kinase abundantly expressed in the brain, plays a pivotal role in AD pathology by increasing β-secretase activity while simultaneously suppressing α-secretase activity(Ly et al., 2013a). This enzymatic imbalance favors the accumulation of Aβ peptides both inside and outside neurons. In AD mouse models, melatonin has been found to inhibit GSK3β activity, potentially through activation of the MT1 melatonin receptor, as demonstrated in studies using SH-SY5Y neuroblastoma cells(Nopparat et al., 2022a). Notably, under hyperglycemic conditions simulated by high glucose exposure, these cells showed impaired glucose sensing, which activated the pAkt/GSK3β signalling cascade. This activation led to increased expression of BACE (β-secretase) and elevated production of the Aβ42 peptide, further contributing to amyloid pathology(Nopparat et al., 2022a). This effect was mitigated when cells were pretreated with melatonin. Additionally, melatonin might influence the clearance of amyloid-beta by modulating the insulin-degrading enzyme (IDE), a key protease responsible for degrading Aβ both inside and outside cells(Kurochkin et al., 2018). In diabetic mouse models, IDE levels are reduced alongside heightened GSK3β activity in the CNS(Jolivalt et al., 2008). Notably, a synthesized compound combining melatonin and the metal chelator trientine, referred to as melatonin-trientine was found to increase IDE expression, reduce Aβ buildup, and prevent neuronal degeneration in the brains of APP/Presenilin 1 mice(Li et al., 2022).
Another way melatonin exerts its anti-amyloidogenic effects is by promoting the removal of Aβ from the brain. Astrocytes, located at the boundary between brain tissue and the perivascular space which contains capillaries, larger arteries, and veins are involved in clearing Aβ through processes such as enzymatic breakdown and by increasing the activity of efflux transporters for Aβ at the blood-brain barrier (Bechmann et al., 2007). Research using mouse neuroblastoma cells (Neuro-2a) indicates that melatonin may enhance the expression of Transcription Factor EB, a key regulator of lysosome formation. This, in turn, facilitates the clearance of Aβ by astrocytes through the autophagosome-lysosome pathway (Thal, 2012).
Studies have proved that melatonin upregulates the expression of low-density lipoprotein receptor-related protein 1 (LRP1), which is a key receptor involved in transporting Aβ across the BBB and mediating its uptake by astrocytes enhances the clearance of Aβ (Promyo et al., 2020a). Apolipoprotein E (ApoE),a protein involved in lipid transport via cell surface receptors can possibly interfere with this process. ApoE competes with Aβ for LRP1-mediated uptake, and hence hinders the process of Aβ clearance, thereby contributing towards its accumulation and plaque formation in the brain(Hatters et al., 2006). Research in the past decades have depicted that, in astrocytes derived from transgenic AD mouse models that overexpress ApoE, melatonin has been found to counteract ApoE's pro-aggregation effects on Aβ(Verghese et al., 2013). Clinical studies have reported that individuals who have the high-risk APOE4/4 genotype do exhibit lower melatonin levels in cerebrospinal fluid that are at a level that is close to half what individuals carrying just one APOE4 allele have, suggesting such individuals may gain benefit from melatonin supplementation(R. Y. Liu et al., 1999b; Poeggeler et al., 2001).
There are several clinical models established which extensively elucidate melatonin’s role in Aβ neurotoxicity and production/clearance mechanisms. Besides helping the brain’s support cells (astrocytes) clear out waste, melatonin might also ease the buildup of Aβ by boosting the brain’s lymphatic drainage system. In a mouse model of AD (Tg2576), which has a gene mutation causing excess Aβ in the brain, melatonin treatment seemed to shift more Aβ to the lymph nodes in the neck and armpits, while Aβ levels in the brain showed signs of decreasing. Studies conducted by (O’Neal-Moffitt et al., 2015a) illustrates how melatonin reduces Aβ production, by interfering with amyloid fibril formation, and thereby decreasing Aβ deposition in transgenic mouse brains; whereas chronic supplementation improved spatial memory in APP/PS1 mice.
Preclinical evidence across diverse animal models including transgenic APP/PS1 and Tg2576 mice, senescence-accelerated SAMP8 mice, and Aβ-infused or toxin-induced rats consistently demonstrates that melatonin mitigates amyloid-β neurotoxicity(O’Neal-Moffitt et al., 2015a). It inhibits amylodgenesis, prevents fibril aggregation, restores mitochondrial and antioxidant defenses, and improves cognition(Dragicevic et al., 2011a; Matsubara, Bryant-Thomas, et al., 2003; Olcese et al., 2009). These findings collectively support melatonin’s multifaceted neuroprotective potential against the amyloidogenic cascade of AD.
C. Limitations
Despite substantial preclinical evidence supporting melatonin’s neuroprotective actions against amyloid-β toxicity, several factors limit its direct translation to human studies. These include the use of excessively high doses, simplified or incomplete AD models, insufficient attention to circadian timing and sex differences, and interventions initiated before significant disease manifestation. In addition, inconsistencies in experimental protocols and potential publication bias hinder reproducibility and clinical relevance. Overcoming these challenges through standardized methodologies, use of aged and multifactorial animal models, and incorporation of chronopharmacological approaches will be essential to translate preclinical findings into meaningful clinical outcomes.
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