Using a novel mTBI model to investigate phosphorylation dependent common mechanisms in tauopathies

使用新型 mTBI 模型研究 tau蛋白病的磷酸化依赖性常见机制

• 批准号: 10369078
• 负责人: TIMOTHY J EBNER
• 金额: $ 76.73万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10369078
• 关键词: Affect; Age; Alzheimer' s Disease; Antibodies; Biochemical; Brain; CDK5 gene; Calcium; Cells; Cerebral cortex; Cultured Cells; Dementia; Dendritic Spines; Disease; Disease Progression; Electrophysiology (science); Event; Functional disorder; Genes; Goals; Hippocampus (Brain); Human; Image; Impairment; Inclusion Bodies; Knowledge; Label; Mechanics; Mediating; Modeling; Modification; Molecular; Morphology; Mus; Mutation; Neurodegenerative Disorders; Outcome; PHF-1; Pathogenicity; Pathology; Peptides; Phosphorylation; Physiological; Play; Polymers; Post-Translational Protein Processing; Process; Protein Isoforms; Publishing; Recovery; Research Priority; Role; Series; Severities; Signal Transduction; Slice; Synapses; Synaptic plasticity; System; Tauopathies; Testing; Therapeutic; Therapeutic Intervention; Work; base; density; experimental study; human disease; inhibitor; juvenile animal; mild traumatic brain injury; mouse model; neural circuit; novel; postsynaptic; prevent; synaptic function; tau Proteins; tau aggregation; tau phosphorylation; tau-1; therapeutically effective; tool

Alzheimer’s disease (AD) and many related dementias (ADRDs) are tauopathies, characterized by somatodendritic accumulation of tau and intraneuronal inclusion bodies composed of tau species that have undergone extensive post translational modification. Although some disease-specific Tau modifications have been identified, many are conserved across the full range of tauopathies. We do not yet have a deep understanding of the molecular processes that generate these tau protein modifications, or of their functional consequences in promoting pathogenic cascades. This knowledge gap is a major contributor to our current inability to generate effective therapeutic interventions for AD and other tauopathies. The central hypothesis we are testing here is that a range of pathogenic events induce phosphorylation of tau at specific residues, resulting in mislocalization of tau within the cell and subsequent synaptic dysfunctions, and that inhibition of these early tau phosphorylation events will in turn inhibit tau pathologies and associated signaling deficits. This hypothesis is based on our published work, primarily utilizing cultured cell experimental systems. The direct relevance of this mechanism to human disease is further supported by the recent finding that phosphorylation of tau at these same specific residues is an early event preceding tau fibril formation in AD disease progression. Our overall objective here is to test and further refine this hypothesis in a novel mouse model we have developed (MAPT- GR) that expresses all isoforms of human tau at physiologic levels and ratios. We have found that mild traumatic brain injury (mTBI) induces a rapid phosphorylation and somatodendritic mislocalization of the human tau in these mice. Importantly, we can prevent this tau mislocalization by inhibiting phosphorylation. The specific aims are to: 1. Determine the dynamic changes in the subcellular distribution of phosphorylated tau. We will utilize our novel tauopathy model to test the working hypothesis that phosphorylation of tau at specific residues leads to somatodendritic accumulation of tau, tau mislocalization to dendritic spines, and alters micro- components of dendritic spines. 2. Determine the synaptic and circuit dysfunctions associated with the phosphorylation of tau. We will test the working hypothesis that mislocalization of phosphorylated tau to somatodendritic domains and dendritic spines results in synaptic and circuit dysfunction in our model. 3. Identify the impact of inhibiting these early phosphorylation events on tau mislocalization and associated signaling deficits. We will test our working hypothesis that mTBI activates GSK3β and CDK5, which phosphorylate the B and C domain of the tau protein. Expected Outcomes: We expect to identify the early-stage pathologies and dysfunctions caused by phosphorylation of tau and provide proof-of-concept demonstrations of the extent to which these dysfunctions can be prevented by blocking tau phosphorylation at specific residues. Of equal importance, we expect to have optimized a model and experimental platform in which potential therapeutic compounds that target this common disease mechanism can be tested and optimized.

阿尔茨海默病（AD）和许多相关痴呆（ADRD）是tau蛋白病，其特征在于 tau的体树突积累和由tau种类组成的神经元内包涵体， 经历了广泛的翻译后修饰。尽管一些疾病特异性Tau修饰具有 已经鉴定，许多在整个tau蛋白病范围内是保守的。我们还没有一个深刻的 了解产生这些tau蛋白修饰的分子过程，或其功能 促进致病级联的后果。这种知识差距是我们目前的主要贡献者 不能产生对AD和其他tau蛋白病的有效治疗干预。核心假设我们 一系列致病事件诱导tau蛋白在特定残基上的磷酸化， 在细胞内tau错误定位和随后的突触功能障碍中， tau磷酸化事件将反过来抑制tau病理和相关的信号传导缺陷。这一假设 基于我们已发表的工作，主要利用培养细胞实验系统。的直接联系 最近的发现进一步支持了这种机制， 相同的特异性残基是AD疾病进展中tau原纤维形成之前的早期事件。我们的整体 本文的目的是在我们开发的新型小鼠模型（MAPT-1）中测试并进一步完善这一假设。 GR），其以生理水平和比率表达人tau的所有同种型。我们发现轻微的创伤 脑损伤（mTBI）诱导人tau蛋白的快速磷酸化和体树突错误定位， 这些老鼠重要的是，我们可以通过抑制磷酸化来防止这种tau蛋白的错误定位。具体目标 1.确定磷酸化tau蛋白亚细胞分布的动态变化。我们将 利用我们的新的tau蛋白病模型来测试工作假设，即tau蛋白在特定残基的磷酸化 导致tau的体树突积累，tau错误定位于树突棘，并改变微- 树枝刺的组成部分。2.确定突触和电路功能障碍与 tau的磷酸化。我们将测试工作假设，即磷酸化tau蛋白的错误定位， 在我们的模型中，体树突结构域和树突棘导致突触和回路功能障碍。3.识别 抑制这些早期磷酸化事件对tau蛋白错误定位和相关的 信号缺陷我们将测试我们的工作假设，即mTBI激活GSK 3 β和CDK 5， 磷酸化tau蛋白的B和C结构域。预期成果：我们希望确定早期阶段 病理和功能障碍引起的tau蛋白磷酸化，并提供了概念验证的示范， 这些功能障碍可以通过阻断特定残基的tau磷酸化来预防的程度。 同样重要的是，我们希望优化一个模型和实验平台， 可以测试和优化靶向这种常见疾病机制的治疗化合物。