Jiang Gege, Xie Guanfeng, Li Xiaoyi, Xiong Jing
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430000, China.
Biomolecules. 2025 Jun 6;15(6):831. doi: 10.3390/biom15060831.
The aggregation of Tau protein into neurofibrillary tangles (NFTs), a hallmark of Alzheimer's disease (AD), is associated with cognitive decline. Recent studies have revealed that neuronal cytoskeletal instability drives early AD pathogenesis. The physiological interaction between tau and the microtubule (MT) is crucial for maintaining axonal transport and stability. However, aberrant post-translational modifications (PTMs) in the MT binding domain-such as phosphorylation, acetylation and ubiquitination-trigger tau dissociation, causing microtubule collapse, transport deficits, and synaptic dysfunction. MT dysregulation also affects actin/cofilin-mediated dendritic spine destabilization and causes the hyperplasia of the glial intermediate filament, which exacerbates neuroinflammation and synaptic toxicity. This review systematically explores the functions of neuronal cytoskeletons, deciphers the molecular crosstalk between tau pathology and cytoskeletal remodeling, and proposes multi-target therapeutic strategies to restore cytoskeletal homeostasis, thereby providing novel perspectives for precision interventions in AD.
tau蛋白聚集成神经原纤维缠结（NFTs）是阿尔茨海默病（AD）的一个标志，与认知能力下降有关。最近的研究表明，神经元细胞骨架不稳定驱动早期AD发病机制。tau蛋白与微管（MT）之间的生理相互作用对于维持轴突运输和稳定性至关重要。然而，MT结合域中的异常翻译后修饰（PTM），如磷酸化、乙酰化和泛素化，会引发tau蛋白解离，导致微管塌陷、运输缺陷和突触功能障碍。MT失调还会影响肌动蛋白/丝切蛋白介导的树突棘不稳定，并导致神经胶质中间丝增生，从而加剧神经炎症和突触毒性。本综述系统地探讨了神经元细胞骨架的功能，解读了tau病理与细胞骨架重塑之间的分子相互作用，并提出了恢复细胞骨架稳态的多靶点治疗策略，从而为AD的精准干预提供新的视角。
