华中科技大学王建枝等研究人员合作开发出一种用于治疗tau病的新型tau去磷酸化靶向嵌合体。这一研究成果于2024年7月2日在线发表在国际学术期刊《中国药理学报》上。

研究人员表示，高磷酸化tau蛋白的异常积累在包括阿尔茨海默病（AD）在内的一系列被称为tau病的神经退行性疾病中起着关键作用。研究人员最近构思设计了异质双功能嵌合体，用于选择性地促进tau和磷酸酶之间的接近，从而专门促进tau去磷酸化和清除。

Title: A new tau dephosphorylation-targeting chimera for the treatment of tauopathies

Author: Su, Jing-fen, Xiao, Yue, Wei, Lin-yu, Lei, Hui-yang, Sun, Fei, Wang, Wei-xia, Li, Shi-hong, Wang, Xiao-chuan, Zheng, Jie, Wang, Jian-zhi

Issue&Volume: 2024-07-02

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.

DOI: 10.1038/s41401-024-01326-4

Source: https://www.nature.com/articles/s41401-024-01326-4