Evaluation and Disruption of Tau - GSK3β Vicious Cycle

项目总结/摘要 我们的目标是提高我们对阿尔茨海默病的理解和治疗能力。我们的实验室发现， 减少可以阻止A β诱导的GSK3 β激活，GSK3 β是一种由许多AD相关的 病理机制，并与tau蛋白的过度磷酸化有关。我们将决定 这些机制以tau依赖的方式激活GSK 3 β，并且激活是否涉及直接的 tau和GSK3 β之间的相互作用。为了防止tau依赖性GSK 3 β激活，我们建议减少 总体tau水平。Tau减少可以预防AD小鼠模型中的认知下降和神经变性。 我们发现，阻断rho相关蛋白激酶（ROCK）通路可以降低原代细胞中的tau蛋白水平。 和成年小鼠脑中。为了进一步探索这种治疗策略，我们将使用一种新的ROCK抑制剂， 在小鼠模型中具有高效力和良好的脑渗透性。

Project Summary/Abstract Our goal is to advance our understanding and ability to treat Alzheimer's disease. Our lab discovered that tau reduction can prevent Aβ-induced activation of GSK3β, a kinase that is activated by many AD-relevant pathomechanisms and has been implicated in the hyperphosphorylation of tau. We will determine which of these mechanisms activate GSK3β in a tau-dependent manner and whether the activation involves direct interactions between tau and GSK3β. To prevent tau-dependent GSK3β activation, we propose to reduce overall tau levels. Tau reduction can prevent cognitive decline and neurodegeneration in mouse models of AD. We found that blocking the rho-associated protein kinase (ROCK) pathway reduces tau levels in primary cells and in adult mouse brain. To further explore this therapeutic strategy, we will use a new ROCK inhibitor that has high potency and good brain penetration in mouse models.