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: 10625988
• 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/10625988
• 关键词: Affect; Age; Alzheimer' s Disease; Antibodies; Biochemical; Body Composition; Brain; CDK5 gene; Calcium; Cells; Cerebral cortex; Cultured Cells; Dementia; Dendritic Spines; Disease; Disease Progression; Early identification; Electrophysiology (science); Event; Functional disorder; Genes; Goals; Hippocampus; Human; Image; Impairment; Inclusion Bodies; Knowledge; Label; Mechanics; Mediating; Modeling; Modification; Molecular; Morphology; Mus; Mutation; Neurodegenerative Disorders; Outcome; PHF-1; Pathogenicity; Pathology; Peptides; Phosphorylation; Phosphorylation Inhibition; 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; density; experimental study; glycogen synthase kinase 3 beta; human disease; inhibitor; juvenile animal; mild traumatic brain injury; mouse model; neural circuit; novel; postsynaptic; prevent; synaptic function; tau Proteins; tau aggregation; 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)和许多相关痴呆症(ADRD)是一种自发性疾病，其特征是 Tau的体树突状堆积和由tau物种组成的神经元内包涵体 进行了广泛的翻译后修改。尽管一些针对疾病的TAU修改具有 已经被发现，许多在所有的牛角病中都是保守的。我们还没有一个很深的 理解产生这些tau蛋白修饰的分子过程，或它们的功能 促进致病级联的后果。这一知识鸿沟是我们目前 无法为阿尔茨海默病和其他焦虑症制定有效的治疗干预措施。我们的中心假设是 在这里测试的是一系列致病事件诱导特定残基tau的磷酸化，结果 在细胞内tau错误定位和随后的突触功能障碍，以及对这些早期功能的抑制 Tau磷酸化事件将反过来抑制tau病理和相关的信号缺陷。这一假设 是基于我们发表的工作，主要是利用培养细胞实验系统。的直接关联性 最近的发现进一步支持了人类疾病的这种机制，即tau在这些基因上的磷酸化 在AD疾病进展中，相同的特定残留物是tau纤维形成之前的早期事件。我们的整体 目标是在我们开发的一种新的小鼠模型(MAPT-MAPT)中测试并进一步完善这一假说。 GR)，它在生理水平和比例上表达人类tau的所有亚型。我们发现轻微的创伤 脑损伤(MTBI)诱导人tau蛋白快速磷酸化和躯体树突状细胞定位错误 这些老鼠。重要的是，我们可以通过抑制磷酸化来防止tau的错误定位。具体目标 目的：1.测定磷酸化tau亚细胞分布的动态变化。我们会 利用我们新的肌病模型来检验特定残基上tau的磷酸化的工作假说 导致tau的体树突状堆积，tau错误定位于树突棘，并改变微-树突棘。 树突棘的成分。2.确定与突触和环路功能障碍相关的 Tau的磷酸化。我们将检验工作假设，即磷酸化tau的错误定位为 在我们的模型中，躯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错误定位和相关的影响 信号缺陷。我们将检验我们的工作假设，即mTBI激活Gsk3β和CDK5，这是 使tau蛋白的B和C结构域磷酸化。预期结果：我们希望确定早期阶段 由tau的磷酸化引起的病理和功能障碍，并提供概念验证演示 通过阻止特定残基的tau磷酸化可以防止这些功能障碍的程度。 同样重要的是，我们希望优化一个模型和实验平台，在其中 针对这种常见疾病机制的治疗化合物可以进行测试和优化。