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.

中文翻译：

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tau 去磷酸化靶向嵌合体选择性募集蛋白磷酸酶-1 以改善阿尔茨海默病和 tau 蛋白病


过度磷酸化 tau （pTau） 的异常积累是阿尔茨海默病 （AD） 和相关 tau 蛋白病神经退行性变的主要原因。因此，减少 pTau 对这些疾病具有治疗前景。在这里，我们开发了一种名为 D20 的嵌合肽，通过向 tau 募集蛋白磷酸酶 1 （PP1） 来选择性促进 tau 去磷酸化。PP1 是使 tau 去磷酸化的活性磷酸酶之一。在培养的原代海马神经元和 AD 或相关 tau 蛋白病的小鼠模型中，我们证明单剂量 D20 治疗通过在多个 AD 相关位点的去磷酸化显着降低 pTau，并且总 tau （tTau） 水平也降低。在 3xTg AD 小鼠中通过尾静脉注射多剂量施用 D20 可有效改善 tau 相关病理，改善认知功能。重要的是，在治疗剂量下，D20 不会在小鼠培养的神经元、神经细胞或外周器官中引起可检测的毒性。这些结果表明，D20 是 AD 和相关 tau 蛋白病的有前途的候选药物。