Development of tau phosphorylation-targeting therapies for the treatment of neurodegenerative diseases

作者：Jingfen Su, Yue Xiao, Xiaochuan Wang, Jie Zheng, Jian‐Zhi Wang · 发表于：Medicine Plus · 年份：2024 · DOI：10.1016/j.medp.2024.100060 · 被引用次数：15 · 研究领域：Alzheimer's disease research and treatments、Neurological Disorders and Treatments、Cholinesterase and Neurodegenerative Diseases

Hyperphosphorylation of microtubule-associated protein tau is a major driver in the etiology of multiple neurodegenerative diseases, such as Alzheimer’s disease (AD) and other tauopathies. Intracellular accumulation of hyperphosphorylated tau (pTau) decreases microtubule stability, induces protein aggregation, and impairs neuronal plasticity. Increasing attention has been devoted to the development of targeted therapies for modulating tau phosphorylation, including conventional protein kinase inhibitors, phosphatase activators, immunotherapies, as well as a new collection of tau-targeted hetero-bifunctional chimeras such as dephosphorylation-targeting chimeras (DEPTACs), proteolysis targeting chimeras (PROTACs) for pTau, phosphorylation targeting chimeras (phosTACs), and affinity-directed phosphatase (AdPhosphatase) system. In this review, we briefly introduce tau and its role in neurodegenerative diseases, provide progress in the development of pTau targeting therapies, and discuss their advantages and limitations.