A new tau dephosphorylation-targeting chimera for the treatment of tauopathies

Abnormal accumulation of hyperphosphorylated tau protein plays a pivotal role in a collection of neurodegenerative diseases named tauopathies, including Alzheimer’s disease (AD). We have recently conceptualized the design of hetero-bifunctional chimeras for selectively promoting the proximity betwee...

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Bibliographic Details
Published in:Acta pharmacologica Sinica 2024-11, Vol.45 (11), p.2267-2276
Main Authors: Su, Jing-fen, Xiao, Yue, Wei, Lin-yu, Lei, Hui-yang, Sun, Fei, Wang, Wei-xia, Li, Shi-hong, Wang, Xiao-chuan, Zheng, Jie, Wang, Jian-zhi
Format: Article
Language:English
Subjects:
Biomedical and Life Sciences
Biomedicine
Immunology
Internal Medicine
Medical Microbiology
Pharmacology/Toxicology
Vaccine
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Summary:Abnormal accumulation of hyperphosphorylated tau protein plays a pivotal role in a collection of neurodegenerative diseases named tauopathies, including Alzheimer’s disease (AD). We have recently conceptualized the design of hetero-bifunctional chimeras for selectively promoting the proximity between tau and phosphatase, thus specifically facilitating tau dephosphorylation and removal. Here, we sought to optimize the construction of tau dephosphorylating-targeting chimera (DEPTAC) and obtained a new chimera D14, which had high efficiency in reducing tau phosphorylation both in cell and tauopathy mouse models, while showing limited cytotoxicity. Moreover, D14 ameliorated neurodegeneration in primary cultured hippocampal neurons treated with toxic tau-K18 fragments, and improved cognitive functions of tauopathy mice. These results suggested D14 as a cost-effective drug candidate for the treatment of tauopathies.
ISSN:1671-4083
1745-7254
1745-7254
DOI:10.1038/s41401-024-01326-4