华中科技大学Jian-Zhi Wang等研究人员合作发现，tau去磷酸化的靶向嵌合体可治疗阿尔茨海默病和相关的tau病理。相关论文于2024年1月19日在线发表于国际学术期刊《科学通报》。

研究人员构想出了一种名为去磷酸化靶向嵌合体（DEPTAC）的策略，用于特异性地将磷酸酶劫持到tau上，以削弱其过度磷酸化。研究人员对每个组成基团进行了逐步优化，以产生在促进病理tau的去磷酸化和随后清除方面具有合理有效性的DEPTAC。具体来说，对于所选嵌合体之一的D16，研究人员在体外实验中证明了它在挽救由神经毒性K18-tau种子引起的神经退行性变方面的显著功效。

此外，静脉注射D16还能缓解阿尔茨海默病（AD）小鼠大脑中的tau病变，并改善记忆缺陷。这些结果表明，DEPTAC是tau磷酸化的靶向调节剂，具有治疗AD和其他tau病理的潜力。

据悉，tau蛋白的异常高磷酸化和积累在AD和许多其他tau病理的神经变性中起着关键作用。选择性消除高磷酸化tau蛋白有望治疗这些疾病。

附：英文原文

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

Author: anonymous

Issue&Volume: 2024/01/19

Abstract: Abnormal hyperphosphorylation and accumulation of tau protein play a pivotal role in neurodegeneration in Alzheimer’s disease (AD) and many other tauopathies. Selective elimination of hyperphosphorylated 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 debilitate 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 subsequent clearance of pathological tau. Specifically, for one of the selected chimeras, D16, we demonstrated its significant efficiency in rescuing the neurodegeneration caused by neurotoxic K18-tau seeds in vitro. Moreover, intravenous administration of D16 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.

DOI: 10.1016/j.scib.2024.01.019

Source: https://www.sciencedirect.com/science/article/pii/S2095927324000379