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.
摘要：
tau蛋白的异常过度磷酸化和积累在阿尔茨海默病（AD）和许多其他tau蛋白病变的神经变性中起关键作用。选择性消除过度磷酸化的tau有望用于治疗这些疾病。我们已经概念化了一个战略，命名为去磷酸化靶向嵌合体（DEPTACs），专门劫持磷酸酶到tau以削弱其过度磷酸化。这里,我们对每个组成基序进行了逐步优化,以生成具有促进去磷酸化和随后清除病理性tau的合理有效性的DEPTACs.具体来说,对于其中一个选定的嵌合体，D16，我们证明了其在体外挽救由神经毒性K18-tau种子引起的神经变性的显着效率。此外，D16的静脉内给药还减轻了AD小鼠脑中的tau病理并改善了记忆缺陷。这些结果表明DEPTAC作为tau磷酸化的靶向调节剂，对AD和其他tau蛋白病具有治疗潜力。
