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

作　　者：Jing-fen Su Yue Xiao Lin-yu Wei Hui-yang Lei Fei Sun Wei-xia Wang Shi-hong Li Xiao-chuan Wang Jie Zheng Jian-zhi Wang 

机构地区：[1]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 [2]School of Artificial Intelligence and Automation,Huazhong University of Science and Technology,Wuhan,430030,China [3]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 [4]Department of Anesthesiology,the First Affiliated Hospital of Gannan Medical University,Ganzhou,341000,China [5]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 [6]Beijing Life Science Academy,Beijing,102209,China [7]Co-innovation Center of Neuroregeneration,Nantong University,Nantong,226000,China

出　　处：《Acta Pharmacologica Sinica》2024年第11期2267-2276,共10页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(No.82230041,91949205);Sanming Project of Medicine in Shenzhen(No.SZSM202211010);Guangdong Provincial Key S&T Program(No.2018B030336001),Peking University Talent Startup Fund(No.BMU2022YJ003);supported by the“Fundamental Research Funds for the Central Universities”,Scientific Project of Beijing Life Science Academy(No.2024300CC0020).

摘　　要：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.

关 键 词：TAU dephosphorylation targeting chimera(DEPTAC) TAUOPATHY Alzheimer’s disease drug development 

分 类 号：R96[医药卫生—药理学]