Fig. 3: Melatonin’s role in mitigating tau hyperphosphorylation and neurofibrillary tangles formation in Alzheimer’s disease.

Tau, a microtubule-associated protein crucial for the structural integrity of neurons, undergoes hyperphosphorylation in Alzheimer’s disease (AD), leading to the accumulation of phosphorylated tau and the formation of neurofibrillary tangles (NFTs). This hyperphosphorylation compromises tau’s ability to support microtubule assembly, contributing to the development of NFTs in neurons. Furthermore, NFTs and hyperphosphorylated tau can induce oxidative stress in neurons, primarily through mitochondrial dysfunction. Oxidative stress may also activate kinases associated with tau hyperphosphorylation, including glycogen synthase kinase-3β (GSK3β), cyclin-dependent kinase 5 (CDK5), and protein kinase A (PKA). Increased oxidative stress acting on neurons can also result from amyloid β (Aβ)-driven activation of microglia through toll-like receptor 4 (TLR4) or interactions with transition metals in the brain interstitial fluid, leading to an abundance of reactive oxygen species (ROS) and reactive nitrogen species (RNS). As elucidated in Section Melatonin’s Potential to Counteract Tau Pathology, melatonin exhibits promising potential in mitigating tau hyperphosphorylation, as demonstrated in both animal models of AD and cell line experiments. Through its robust antioxidative potential, melatonin may hinder the oxidative stress-induced activation of protein kinases involved in tau hyperphosphorylation. Additionally, the hormone, via activation of its melatonin receptor 1, reduces the activity of GSK3β, showcasing another anti-tauogenic effect. Melatonin further engages in the activation of enzymes that counteract tau hyperphosphorylation. For instance, it upregulates the activity of phosphatase 2 A (PP2A), recognized for its role in dephosphorylating tau, and elevates levels of Peptidyl-Prolyl cis-trans Isomerase NIMA-Interacting 1 (Pin1), crucial for restoring tau function.