多肽靶向嵌合体通过促进tau蛋白特异性去磷酸化治疗阿尔茨海默病和其他tau蛋白病  

Generation of tau dephosphorylation-targeting chimeras for the treatment of Alzheimer's disease and related tauopathies

作　　者：苏静芬 肖越 魏林郁 雷慧杨 孙飞 王围霞 尹君 熊瑞 李师宏 张配 周颖 王小川 郑杰 王建枝 Jingfen Su;Yue Xiao;Linyu Wei;Huiyang Lei;Fei Sun;Weixia Wang;Jun Yin;Rui Xiong;Shihong Li;Pei Zhang;Ying Zhou;Xiaochuan Wang;Jie Zheng;Jian-Zhi Wang(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;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;Department of Pathophysiology,School of Basic Medical Sciences,Wuhan University,Wuhan 430030,China;Department of Anesthesiology,The First Affiliated Hospital of Gannan Medical University,Ganzhou 341000,China;The Core Facility and Technical Support,Wuhan Institute of Virology,Chinese Academy of Sciences,Wuhan 430030,China;Research Center for Medicine and Structural Biology,Wuhan University,Wuhan 430030,China;Neuroscience Research Institute and Department of Neurobiology,School of Basic Medical Sciences,Peking University,Key Laboratory for Neuroscience,Ministry of Education/National Health Commission,Beijing 100083,China;Co-innovation Center of Neuroregeneration,Nantong University,Nantong 226000,China)

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 Pathophysiology,School of Basic Medical Sciences,Wuhan University,Wuhan 430030,China [5]Department of Anesthesiology,The First Affiliated Hospital of Gannan Medical University,Ganzhou 341000,China [6]The Core Facility and Technical Support,Wuhan Institute of Virology,Chinese Academy of Sciences,Wuhan 430030,China [7]Research Center for Medicine and Structural Biology,Wuhan University,Wuhan 430030,China [8]Neuroscience Research Institute and Department of Neurobiology,School of Basic Medical Sciences,Peking University,Key Laboratory for Neuroscience,Ministry of Education/National Health Commission,Beijing 100083,China [9]Co-innovation Center of Neuroregeneration,Nantong University,Nantong 226000,China

出　　处：《Science Bulletin》2024年第8期1137-1152,共16页科学通报（英文版）

基　　金：supported by the National Natural Science Foundation of China(82230041,91949205,31730035,81721005);the National Key R&D Program of China(2016YFC1305800);the Guangdong Provincial Key S&T Program(018B030336001)。

摘　　要：Abnormal hyperphosphorylation and accumulation of tau protein play a pivotal role in neurodegeneration in Alzheimer’s disease(AD)and many other tauopathies.Selective elimination of hyperphosphorylated tau is promising for the therapy of these diseases.We have conceptualized a strategy,named dephosphorylation-targeting chimeras(DEPTACs),for specifically hijacking phosphatases to tau to debilitate its hyperphosphorylation.Here,we conducted the step-by-step optimization of each constituent motif to generate DEPTACs with reasonable effectiveness in facilitating the dephosphorylation and subsequent clearance of pathological tau.Specifically,for one of the selected chimeras,D16,we demonstrated its significant efficiency in rescuing the neurodegeneration caused by neurotoxic K18-tau seeds in vitro.Moreover,intravenous administration of D16 also alleviated tau pathologies in the brain and improved memory deficits in AD mice.These results suggested DEPTACs as targeted modulators of tau phosphorylation,which hold therapeutic potential for AD and other tauopathies.

关 键 词：TAU Dephosphorylation-targeting chimeras Therapeutic potential TAUOPATHY 

分 类 号：R749.16[医药卫生—神经病学与精神病学]