Tau dysfunction in alzheimer's disease: molecular and cellular mechanisms, genetic modulation, and therapeutic perspectives.

Amyloid-beta (Aβ) plaque formation and tauopathy are two of several hallmarks of Alzheimer's disease (AD), a neurodegenerative disease. AD's widely known pathological hallmarks include extracellular amyloid-β deposition, neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein, synaptic dysfunction, neuroinflammation, and cognitive decline. These pathological hallmarks can be explained at the neurochemical level as a loss of biochemical homeostasis in the brain. Dysregulated kinase-phosphatase signalling, altered post-translational modifications, and disrupted synaptic neurochemistry eventually push tau protein towards its pathological aggregation-prone form. Among these hallmarks, recent research has found that tau pathology plays a major role in neurodegeneration and cognitive decline. Tau protein typically acts as a microtubule-stabilizing protein that helps maintain neuronal structure. In AD, pathological hyperphosphorylation, post-translational modifications, and redistribution of tau trigger its dysfunction and cytotoxicity. Pathological tau protein accumulates in neurons and undergoes a series of changes that include hyperphosphorylation, aberrant post-translational modifications, missorting, aggregation, fibrillization, and seeding as it spreads between cells. Mutations in APP, PSEN1, and PSEN2 can have downstream effects on tau pathology. Variants in APOE, BIN1, PICALM, CD2AP, and TREM2 also influence tau pathology through cellular pathways including lipid metabolism, endocytic trafficking, proteostasis, and synaptic and neuroimmune mechanisms. These findings support a model in which tau dysfunction results from the convergence of molecular aberrations and genetic susceptibility within a pathological network involving amyloid-β, neuroinflammation, and synaptic failure. This review summarizes tau molecular and cellular mechanisms of tau dysfunction in AD, genetic factors regulating tau pathology, and emerging therapeutic approaches to mitigate tau-mediated neurodegeneration.