A new tau dephosphorylation-targeting chimera for the treatment of tauopathies
Jing-fen Su1,
Yue Xiao1,2,
Lin-yu Wei1,3,
Hui-yang Lei1,
Fei Sun1,
Wei-xia Wang1,
Shi-hong Li4,
Xiao-chuan Wang1,2,
Jie Zheng5,6,7,
Jian-zhi Wang1,8
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
6 Key Laboratory for Neuroscience, Ministry of Education/ National Health Commission, Peking University, Beijing 100083, China
7 Beijing Life Science Academy, Beijing 102209, China
8 Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226000, China
Correspondence to: Xiao-chuan Wang: wangxiaochuan@hust.edu.cn, Jie Zheng: zhengjiie@hsc.pku.edu.cn, Jian-zhi Wang: wangjz@mail.hust.edu.cn,
DOI: 10.1038/s41401-024-01326-4
Received: 21 March 2024
Accepted: 26 May 2024
Advance online: 2 July 2024
Abstract
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.
Keywords:
Tau; dephosphorylation targeting chimera (DEPTAC); tauopathy; Alzheimer’s disease; drug development
