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Evaluation and Disruption of Tau - GSK3ÃÂ² Vicious Cycle

Tau 的评估和破坏 - GSK3™ 恶性循环

基本信息

批准号：
10237411
负责人：
Daniel Gulbranson
金额：
$ 2.33万
依托单位：
J. DAVID GLADSTONE INSTITUTES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2021-12-17
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10237411
关键词：
Adult Adverse effects Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Antisense Oligonucleotides Axonal Transport Binding Blood - brain barrier anatomy Brain Cells Data Development Disease Disease Progression Dose Enterobacteria phage P1 Cre recombinase Evaluation Excision Exposure to Goals Human Immune Impaired cognition Knockout Mice Lead Learning Maintenance Mediating Memory Memory impairment Modeling Mus Nerve Degeneration Neuroglia Neurons Pathogenesis Pathogenicity Pathway interactions Penetration Phosphotransferases Preclinical Testing Process Protein Kinase Proteins Safety Signal Transduction Tauopathies Testing Therapeutic Transgenic Organisms Viral Vector excitatory neuron excitotoxicity experimental study in vivo mouse model mutant neuron loss neuronal survival offspring prevent promoter protein kinase inhibitor rho tau Proteins tau expression tau mutation

项目摘要

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.

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Aβ诱导的GSK 3 β激活，GSK 3 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GSK 3 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。