Hyperphosphorylation of microtubule-associated protein tau is a major driver in the pathogenesis of a variety of neurodegenerative diseases, including 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, they give a brief introduction to tau and its role in neurodegenerative diseases. Mainly, they provide progress in the development of pTau targeting therapies and discuss their advantages and limitations.
https://doi.org/10.1016/j.medp.2024.100060
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