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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Neuropharmacology
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1351792

Selective degradation of hyperphosphorylated tau by proteolysis-targeting chimeras ameliorates cognitive function in Alzheimer's disease model mice

Provisionally accepted
Dongping Yao Dongping Yao 1Ting Li Ting Li 2Lu Yu Lu Yu 1Mingxing Hu Mingxing Hu 1Ye He Ye He 2Ruiming Zhang Ruiming Zhang 1Junjie Wu Junjie Wu 1Shuoyuan Li Shuoyuan Li 1Weihong Kuang Weihong Kuang 3Xifei Yang Xifei Yang 4Gong-Ping Liu Gong-Ping Liu 2*Yongmei Xie Yongmei Xie 1*
  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan Province, China
  • 2 Department of Pathology, Wuhan No. 1 Hospital, Wuhan, China
  • 3 Department of Psychiatry and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
  • 4 Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen, China

The final, formatted version of the article will be published soon.

    Alzheimer's disease (AD) is one of the most common chronic neurodegenerative diseases.Hyperphosphorylated tau plays an indispensable role in neuronal dysfunction and synaptic damage in AD. Proteolysis-targeting chimeras (PROTACs) are a novel type of chimeric molecule that can degrade target proteins by inducing their polyubiquitination. This approach has shown promise for reducing tau protein levels, which is a potential therapeutic target for AD. Compared with traditional drug therapies, the use of PROTACs to reduce tau levels may offer a more specific and efficient strategy for treating AD, with fewer side effects. In the present study, we designed and synthesized a series of small-molecule PROTACs to knock down tau protein. Of these, compound C8 was able to lower both total and phosphorylated tau levels in HEK293 cells with stable expression of wild-type full-length human tau (termed HEK293-htau) and htau-overexpressed mice. Western blot findings indicated that C8 degraded tau protein through the ubiquitin-proteasome system in a time-dependent manner. In htau-overexpressed mice, the results of both the novel object recognition and Morris water maze tests revealed that C8 markedly improved cognitive function. Together, our findings suggest that the use of the small-molecule PROTAC C8 to degrade phosphorylated tau may be a promising therapeutic strategy for AD.

    Keywords: Alzheimer's disease, Hyperphosphorylated tau, PROTACs, targeted protein degradation, Ubiquitine proteasome system

    Received: 07 Dec 2023; Accepted: 20 May 2024.

    Copyright: © 2024 Yao, Li, Yu, Hu, He, Zhang, Wu, Li, Kuang, Yang, Liu and Xie. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Gong-Ping Liu, Department of Pathology, Wuhan No. 1 Hospital, Wuhan, China
    Yongmei Xie, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan Province, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.