Tau phosphorylation homeostasis: Mechanisms, targets, and therapeutic implications in Alzheimer's disease

Neurofibrillary tangles, composed of excessively phosphorylated tau, are a core neuropathological hallmark of Alzheimer's disease (AD). However, therapeutic strategies aimed at directly clearing neurofibrillary tangles have demonstrated limited clinical efficacy, shifting the research focus towards the fundamental underlying mechanism- the dysregulation of tau phosphorylation. Evidence indicates that tau physiological phosphorylation is indispensable for microtubule stability and normal neuronal function, while its aberrant hyperphosphorylation drives neurodegeneration. Consequently, restoring tau phosphorylation homeostasis, rather than merely eliminating the pathological protein, has emerged as a promising therapeutic paradigm. This review systematically delineates the physiological functions and pathological mechanisms of tau phosphorylation, highlighting its central role in AD pathogenesis. We summarize recent advances in drug development targeting key kinases and phosphatases, and discuss the diagnostic value and application prospects of tau phosphorylation biomarkers. Ultimately, this study aims to provide a theoretical framework for novel precision treatment strategies in AD.