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

Autor: Su JF; Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Xiao Y; Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.; School of Artificial Intelligence and Automation, Huazhong University of Science and Technology, Wuhan, 430030, China., Wei LY; Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.; Sino-UK Joint Laboratory of Brain Function and Injury of Henan Province, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, China., Lei HY; Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Sun F; Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Wang WX; Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Li SH; Department of Anesthesiology, the First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China., Wang XC; Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. wangxiaochuan@hust.edu.cn.; School of Artificial Intelligence and Automation, Huazhong University of Science and Technology, Wuhan, 430030, China. wangxiaochuan@hust.edu.cn., Zheng J; Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University; Key Laboratory for Neuroscience, Ministry of Education/National Health Commission, Peking University, Beijing, 100083, China. zhengjiie@hsc.pku.edu.cn.; Beijing Life Science Academy, Beijing, 102209, China. zhengjiie@hsc.pku.edu.cn., Wang JZ; Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. wangjz@mail.hust.edu.cn.; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226000, China. wangjz@mail.hust.edu.cn.
Jazyk: angličtina
Zdroj: Acta pharmacologica Sinica [Acta Pharmacol Sin] 2024 Nov; Vol. 45 (11), pp. 2267-2276. Date of Electronic Publication: 2024 Jul 02.
DOI: 10.1038/s41401-024-01326-4
Abstrakt: 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.
(© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)
Databáze: MEDLINE
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