Evaluation and Disruption of Tau - GSK3β Vicious Cycle

Tau 的评估和破坏 - GSK3β 恶性循环

基本信息

批准号：
10075784
负责人：
Daniel Gulbranson
金额：
$ 6.74万
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 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10075784
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.

项目摘要/摘要我们的目标是提高我们的理解和治疗阿尔茨海默氏病的能力。我们的实验室发现tau 还原可以防止Aβ诱导的GSK3β激活，GSK3β，一种激活的激酶病理机制已在Tau的热磷酸化中暗示。我们将确定哪一个这些机制以tau依赖性的方式激活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依赖性GSK3β激活，我们提议减少总体tau水平。 tau降低可以预防AD小鼠模型中的认知能力下降和神经退行性。我们发现阻止与Rho相关的蛋白激酶（岩石）途径降低了原代细胞中的tau水平和成年小鼠大脑。为了进一步探讨这种理论策略，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大脑渗透。