Hong Xiaoyue, Huang Linshu, Lei Fang, Li Tian, Luo Yi, Zeng Mengliu, Wang Zhuo
Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
Hubei Provincial Clinical Research Center for Molecular Diagnostics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
Biomolecules. 2025 Jun 5;15(6):824. doi: 10.3390/biom15060824.
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 contributions to AD pathogenesis, thereby establishing a framework for biomarker discovery, targeted therapeutic development, and precision medicine approaches in tauopathies. This review synthesizes contemporary advances in tau PTM research and delineates their mechanistic contributions to AD pathogenesis, thereby establishing a solid theoretical and experimental basis for the early diagnosis of neurodegenerative diseases, the discovery of therapeutic targets, and the development of novel therapeutic strategies.
阿尔茨海默病（AD）是一种主要的神经退行性疾病，其临床特征为进行性认知衰退和行为缺陷。深入了解AD的发病机制和神经病理学对于开发有效的治疗方法和早期诊断技术至关重要。AD的神经病理学特征包括两个标志性病变：由过度磷酸化的tau聚集体组成的神经元内神经原纤维缠结和含有淀粉样β（Aβ）肽沉积的细胞外老年斑。尽管在过去三十年中，以Aβ为中心的研究主导了AD研究，但针对Aβ病理的药物干预未能显示出临床疗效。Tau是一种主要定位于神经元轴突的微管相关蛋白，在生理条件下通过动态微管蛋白相互作用协调微管稳定和轴突运输。然而，在AD发病机制中，tau会发生致病性翻译后修饰（PTM），包括过度磷酸化、赖氨酸乙酰化、甲基化、泛素化和糖基化。这些由PTM驱动的改变会导致微管网络解体、线粒体功能障碍、突触损伤和神经炎症级联反应，最终导致不可逆的神经退行性变和进行性认知衰退。本综述综合了tau PTM研究的当代进展，并阐述了它们对AD发病机制的作用机制，从而为tau蛋白病的生物标志物发现、靶向治疗开发和精准医学方法建立了框架。本综述综合了tau PTM研究的当代进展，并阐述了它们对AD发病机制的作用机制，从而为神经退行性疾病的早期诊断、治疗靶点的发现和新型治疗策略的开发奠定了坚实的理论和实验基础。
