Repetitive mTBI-induced neurobehavioral changes and CTE-like proteinopathy

重复性 mTBI 诱导的神经行为变化和 CTE 样蛋白病

• 批准号: 9190335
• 负责人: KEVIN Ka Wang WANG
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-11-01 至 2020-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9190335
• 关键词: Address; Affect; Aggressive behavior; Aging; Anxiety; Behavior; Biochemical; Biological Assay; Biological Markers; Brain; Brain region; Chronic; Chronic Phase; Clinical Research; Closed head injuries; Cognitive; Cognitive deficits; Confusion; Craniocerebral Trauma; DNA-Binding Proteins; Data; Dementia; Deposition; Development; Diagnosis; Enzyme-Linked Immunosorbent Assay; Genetic Crossing Over; Human; Immunization; Immunoassay; Immunotherapeutic agent; Immunotherapy; Impaired cognition; Impairment; Injury; Knowledge; Lead; Learning; Link; Memory Loss; Mental Depression; Military Personnel; Mission; Modeling; Mus; Nerve Degeneration; Nervous System Trauma; Neurologic; Patient Care; Patients; Phase; Phosphorylation; Prevention; Protein Fragment; Proteins; Research; Risk; Rodent; Serum; Symptoms; Testing; Time; Transgenic Mice; Transgenic Organisms; Translating; Veterans; Wild Type Mouse; Work; base; brain tissue; chronic traumatic encephalopathy; combat; depressive symptoms; experience; extracellular; human subject; improved; link protein; meetings; mild traumatic brain injury; mouse model; neurobehavioral; neurobehavioral test; neuropathology; novel; overexpression; oxidation; protein TDP-43; protein aggregate; tau Proteins; tau aggregation; tau-1; tool

Repetitive mild closed head injury (rCHI) is a common form of mild traumatic brain injury (mTBI) among military personnel in both combat and non-combat missions. rCHI can result in sustained cognitive decline and neurobehavioral changes (such as anxiety and depression-like behaviors) [1]. More recently rCHI has also been linked to the formation of a neurodegenerative condition called chronic traumatic encephalopathy (CTE). CTE is pathologically characterized by protein aggregate deposit found in the cortex and other brain regions, post-mortem. Two major proteins found in these CTE protein deposits are microtubule-associated protein Tau and TAR DNA-binding protein (TDP-43) [2-5]. Patients with CTE may show symptoms of dementia, such as memory loss, confusion, anxiety, depression and aggression, which generally appear years or decade(s) after the occurrence of neurotrauma. The Central Hypothesis to be tested is that chronic cognitive and neurobehavioral changes following repetitive mTBI (rCHI) is closely linked to post-injury Tau and TDP-43 proteinopathy development. In addition, the proposed work will not only allow us to test this hypothesis, but also enable us to validate novel CTE biomarkers tests as well as to examine a novel Tau, TDP-43 proteinopathy-based immunotherapy strategy towards improvement of chronic neurobehavioral deficits. Three specific aims are proposed in this application to address the central hypothesis. In Specific Aim 1, we will subject wildtype mice to repetitive close head injury (rCHI) and follow them from subacute to chronic period (up to 18 mo.) to characterize cognitive and neurobehavioral changes, overall neuropathology and their correlation with time-dependent CTE-like Tau/P-tau and TDP-43 protein accumulation /proteinopathy signatures in brain tissue and biofluid. In Specific Aim 2 we will subject human-tau (hTau) transgenic mice and TDP-43 overexpressing transgenic mice to rCHI and follow them from subacute to chronic period to examine if they develop worsened cognitive and neurobehavioral changes, neuropathology and accelerated, exaggerated Tau/TDP-43 proteinopathy signatures in brain tissue and biofluid. Lastly, in Specific Aim 3, we will combine our learning from rCHI models in Aim 1 & 2 to test potential effects of Tau/P-Tau and TDP-43 immunization as novel immunotherapy for reducing rCHI-induced Tau and TDP-43 proteinopathy load and mitigating chronic cognitive, neurobehavioral and neuropathological changes in wildtype, hTau, TDP-43 transgenic and/or hTau/TDP-43 double transgenic mouse lines. This proposed systemic study will advance our understanding of the neurobehavioral (anxiety, depression, cognitive dysfunctions) and their potential linkage to the biochemical/protein changes of aggregation-prone proteins such as Tau and TDP-43 (proteinopathy) and CTE- like neurodegenerative cascade during the chronic phase of TBI. Such knowledge can translate into the ability for VA to devise better management tools and improved Veteran patient care. Our findings will also help us better diagnose chronic TBI including ultrasensitive biofluid-based Tau/P-tau and TDP-43-biomarker tests. Furthermore our research also points to a novel and promising immunotherapeutic strategy to treat such conditions. Taken together, these are all significant biomedical advances consistent with the research mission of the NF/SG VHS and VA and meet the full intent of the RFA. Importantly, the learning from this rodent studies and the immunotherapy approach can rapidly translate into clinical studies with Veterans who are at risk of developing post-TBI CTE.

重复性轻度闭合性颅脑损伤 (rCHI) 是军人中轻度创伤性脑损伤 (mTBI) 的常见形式 执行战斗和非战斗任务的人员。 rCHI 可导致持续的认知能力下降 神经行为变化（例如焦虑和抑郁样行为）[1]。最近，rCHI 还 与称为慢性创伤性脑病（CTE）的神经退行性疾病的形成有关。 CTE 的病理特征是在皮质和其他大脑区域发现蛋白质聚集沉积， 尸检。在这些 CTE 蛋白沉积物中发现的两种主要蛋白是微管相关蛋白 Tau 和 TAR DNA 结合蛋白 (TDP-43) [2-5]。 CTE 患者可能会出现痴呆症状，例如 如记忆丧失、混乱、焦虑、抑郁和攻击性，通常会出现数年或数十年 神经外伤发生后。要测试的中心假设是慢性认知和 重复性 mTBI (rCHI) 后的神经行为变化与损伤后 Tau 和 TDP-43 密切相关 蛋白质病的发展。此外，所提出的工作不仅能让我们检验这个假设，而且 还使我们能够验证新型 CTE 生物标志物测试以及检查新型 Tau、TDP-43 基于蛋白质病的免疫治疗策略，旨在改善慢性神经行为缺陷。三 本申请提出了具体目标来解决中心假设。在具体目标 1 中，我们将 让野生型小鼠遭受重复性近距离头部损伤（rCHI），并跟踪它们从亚急性期到慢性期（向上 至 18 个月）来表征认知和神经行为变化、整体神经病理学及其相关性 大脑中具有时间依赖性 CTE 样 Tau/P-tau 和 TDP-43 蛋白积累/蛋白病特征 组织和生物液。在具体目标 2 中，我们将对人 tau (hTau) 转基因小鼠和 TDP-43 进行实验 过度表达 rCHI 转基因小鼠，并从亚急性期到慢性期跟踪它们，以检查它们是否 认知和神经行为变化恶化，神经病理学变化加速、夸大 脑组织和生物液中的 Tau/TDP-43 蛋白病特征。最后，在具体目标 3 中，我们将结合我们的 从目标 1 和 2 中的 rCHI 模型中学习，以测试 Tau/P-Tau 和 TDP-43 免疫的潜在影响： 用于减少 rCHI 诱导的 Tau 和 TDP-43 蛋白病负荷并缓解慢性疾病的新型免疫疗法 野生型、hTau、TDP-43 转基因和/或的认知、神经行为和神经病理学变化 hTau/TDP-43 双转基因小鼠系。这项拟议的系统研究将增进我们对 神经行为（焦虑、抑郁、认知功能障碍）及其与 易聚集蛋白的生化/蛋白变化，例如 Tau 和 TDP-43（蛋白病）和 CTE- 就像 TBI 慢性期的神经退行性级联反应一样。这些知识可以转化为能力 帮助 VA 设计更好的管理工具并改善退伍军人患者护理。我们的发现也将帮助我们 更好地诊断慢性 TBI，包括基于超灵敏生物流体的 Tau/P-tau 和 TDP-43 生物标志物测试。 此外，我们的研究还指出了一种新颖且有前途的免疫治疗策略来治疗此类疾病 状况。总而言之，这些都是与研究任务相一致的重大生物医学进展 NF/SG VHS 和 VA 并满足 RFA 的全部意图。重要的是，从这种啮齿动物身上学到的东西 研究和免疫治疗方法可以迅速转化为针对退伍军人的临床研究 TBI 后发生 CTE 的风险。