Evaluation and Disruption of Tau - GSK3ò Vicious Cycle

项目摘要/摘要 我们的目标是提高我们对治疗阿尔茨海默病的理解和能力。我们的实验室发现了牛磺酸 还原可以阻止β诱导的Gsk3β的激活，Gsk3是一种被许多AD相关的蛋白激活的激酶 并与tau的过度磷酸化有关。我们将确定哪一位 这些机制以tau依赖的方式激活Gsk3β，以及激活是否涉及直接 Tau和Gsk3β之间的相互作用。为了防止tau依赖的Gsk3β激活，我们建议减少 总的tau水平。降低tau可以防止AD模型小鼠认知功能下降和神经退行性变。 我们发现，阻断Rho相关蛋白激酶(ROCK)通路会降低原代细胞中tau的水平 在成年小鼠的大脑中。为了进一步探索这一治疗策略，我们将使用一种新的岩石抑制剂 在小鼠模型中具有很高的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.