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

扫码查看

原文链接

NETL
NSTL
万方数据

外文摘要：Abnormal hyperphosphorylation and accumulation of tau protein play a pivotal role in neurodegenera-tion in Alzheimer's disease(AD)and many other tauopathies.Selective elimination of hyperphosphory-lated 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 debil-itate 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 sub-sequent clearance of pathological tau.Specifically,for one of the selected chimeras,D1 6,we demon-strated its significant efficiency in rescuing the neurodegeneration caused by neurotoxic K18-tau seeds in vitro.Moreover,intravenous administration of D1 6 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.

外文关键词：

tauDephosphorylation-targeting chimerasTherapeutic potentialTauopathy

作者：

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

展开 >

作者单位：

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

展开 >

基金：

National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Key R&D Program of ChinaGuangdong Provincial Key S&T Program

项目编号：

822300419194920531730035817210052016YFC1305800018B030336001

出版年：

2024

DOI：

10.1016/j.scib.2024.01.019

科学通报(英文版)

中国科学院

科学通报(英文版)

CSTPCD

ISSN：1001-6538

年,卷(期)：2024.69(8)

参考文献量74