The Role and Pathogenesis of Tau Protein in Alzheimer’s Disease

作者：Xiaoyue Hong, Linshu Huang, Fang Lei, Li Tian, Yi Luo, Mengliu Zeng, Zhuo Wang · 发表于：Biomolecules · 年份：2025 · DOI：10.3390/biom15060824 · 被引用次数：36 · 研究领域：Alzheimer's disease research and treatments、Neuroscience and Neuropharmacology Research、Neuroinflammation and Neurodegeneration Mechanisms

Alzheimer's disease (AD), a predominant neurodegenerative disorder, is clinically characterized by progressive cognitive deterioration and behavioral deficits. An in-depth understanding of the pathogenesis and neuropathology of AD is essential for the development of effective treatments and early diagnosis techniques. The neuropathological signature of AD involves two hallmark lesions: intraneuronal neurofibrillary tangles composed of hyperphosphorylated tau aggregates and extracellular senile plaques containing amyloid-β (Aβ) peptide depositions. Although Aβ-centric research has dominated AD investigations over the past three decades, pharmacological interventions targeting Aβ pathology have failed to demonstrate clinical efficacy. Tau, a microtubule-associated protein predominantly localized to neuronal axons, orchestrates microtubule stabilization and axonal transport through dynamic tubulin interactions under physiological conditions. In AD pathogenesis, however, tau undergoes pathogenic post-translational modifications (PTMs), encompassing hyperphosphorylation, lysine acetylation, methylation, ubiquitination, and glycosylation. These PTM-driven alterations induce microtubule network disintegration, mitochondrial dysfunction, synaptic impairment, and neuroinflammatory cascades, ultimately culminating in irreversible neurodegeneration and progressive cognitive decline. This review synthesizes contemporary advances in tau PTM research and delineates their mechanistic contri...