A tau dephosphorylation-targeting chimeraselectively recruits protein phosphatase-1 to ameliorate Alzheimer's disease and tauopathies.

Autor:	Xiao Y; 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; Institute of Artificial Intelligence, Huazhong University of Science and Technology, Wuhan 430074, China., Wei L; 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; Department of Physiology and Pathophysiology, Xinxiang Medical University, Xinxiang 453004, China., Su J; 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., Lei H; 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., Sun F; 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., Li M; 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., Li S; 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; Department of Anesthesiology, The First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China., Wang X; 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; Institute of Artificial Intelligence, Huazhong University of Science and Technology, Wuhan 430074, China. Electronic address: wxch@mails.tjmu.edu.cn., Zheng J; 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; Beijing Life Science Academy, Beijing 102209, China. Electronic address: zhengjiie@hsc.pku.edu.cn., Wang JZ; 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. Electronic address: wangjz@mail.hust.edu.cn.
Jazyk:	angličtina
Zdroj:	Cell chemical biology [Cell Chem Biol] 2024 Oct 17; Vol. 31 (10), pp. 1787-1799.e6. Date of Electronic Publication: 2024 Sep 30.
DOI:	10.1016/j.chembiol.2024.09.003
Abstrakt:	Abnormal accumulation of hyperphosphorylated tau (pTau) is a major cause of neurodegeneration in Alzheimer's disease (AD) and related tauopathies. Therefore, reducing pTau holds therapeutic promise for these diseases. Here, we developed a chimeric peptide, named D20, for selective facilitation of tau dephosphorylation by recruiting protein phosphatase 1 (PP1) to tau. PP1 is one of the active phosphatases that dephosphorylates tau. In both cultured primary hippocampal neurons and mouse models for AD or related tauopathies, we demonstrated that single-dose D20 treatment significantly reduced pTau by dephosphorylation at multiple AD-related sites and total tau (tTau) levels were also decreased. Multiple-dose administration of D20 through tail vein injection in 3xTg AD mice effectively ameliorated tau-associated pathologies with improved cognitive functions. Importantly, at therapeutic doses, D20 did not cause detectable toxicity in cultured neurons, neural cells, or peripheral organs in mice. These results suggest that D20 is a promising drug candidate for AD and related tauopathies. Competing Interests: Declaration of interests We, the authors, have applied for a patent related to this work, and the patent application is pending. (Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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