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.

阿尔茨海默氏病（AD）和许多相关痴呆症（ADRDS）是tauopathies，其特征是 tau和鼻内包含物体的体体积累，该物种由具有 经过了广泛的翻译后修改。尽管某些特异性tau修饰具有 我们还没有深 了解产生这些TAU蛋白质修饰或其功能的分子过程 促进致病性级联反应的后果。这个知识差距是我们当前的主要贡献者 无法为AD和其他tauopath产生有效的治疗干预措施。中心假设我们 这里的测试是，一系列致病事件在特定结果下诱导Tau的磷酸化，从而导致 在细胞内tau的错误定位和随后的突触功能障碍，并抑制这些早期 tau磷酸化事件将依次抑制tau病理和相关的信号不足。这个假设 是基于我们发表的工作，主要利用培养的细胞实验系统。直接相关性 最近的发现，tau的磷酸化在这些机制进一步支持了这种机制 相同的特定残留物是在AD疾病进展中形成tau纤维之前的早期事件。我们的整体 这里的目的是在我们开发的新型小鼠模型中检验并进一步完善这一假设（MAPT- gr）以生理水平和比率表达人tau的所有同工型。我们发现轻度创伤 脑损伤（MTBI）诱导了人类在 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错误定位。具体目标 为：1。确定磷酸化tau的亚细胞分布的动态变化。我们将 利用我们的新型陶氏病模型来测试tau在特定残差处磷酸化的工作假设 导致tau的体积积累，tau误差为树突状刺，并改变微型 树突状刺的成分。 2。确定与 tau的磷酸化。我们将检验以下假设，即磷酸化的tau将磷酸化的定位错误地定位到 在我们的模型中，体生成域和树突状刺会导致突触和电路功能障碍。 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。我们将测试MTBI激活GSK3β和CDK5的工作假设，这 磷酸化tau蛋白的B和C结构域。预期结果：我们希望确定早期 由TAU的磷酸化引起的病理和功能障碍，并提供了概念验证的证明 通过在特定保留下阻止tau磷酸化来预防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，潜在的平台 可以测试和优化靶向这种常见疾病机制的治疗化合物。