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

Jingfen Su ¹Yue Xiao ²Linyu Wei ³Huiyang Lei ¹Fei Sun ¹Weixia Wang ¹Jun Yin ⁴Rui Xiong ¹Shihong Li ⁵Pei Zhang ⁶Ying Zhou ⁷Xiaochuan Wang ²Jie Zheng ⁸Jian-Zhi Wang⁹

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作者信息

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. 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
3. 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
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. 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;Co-innovation Center of Neuroregeneration,Nantong University,Nantong 226000,China
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Abstract

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.

Key words

tau/Dephosphorylation-targeting chimeras/Therapeutic potential/Tauopathy

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基金项目

National Natural Science Foundation of China(82230041)

National Natural Science Foundation of China(91949205)

National Natural Science Foundation of China(31730035)

National Natural Science Foundation of China(81721005)

National Key R&D Program of China(2016YFC1305800)

Guangdong Provincial Key S&T Program(018B030336001)

出版年

2024

科学通报(英文版)

中国科学院

科学通报(英文版)

CSTPCD

ISSN：1001-6538

参考文献量74

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