Repetitive mTBI-induced neurobehavioral changes and CTE-like proteinopathy

重复性轻度闭合性颅脑损伤（rCHI）是军人中常见的轻度创伤性脑损伤（mTBI） 在战斗和非战斗任务中。rCHI可导致持续的认知能力下降， 神经行为改变（如焦虑和抑郁样行为）[1]。最近，rCHI还 与一种称为慢性创伤性脑病（CTE）的神经退行性疾病的形成有关。 CTE的病理学特征是在皮层和其他脑区域中发现的蛋白质聚集存款， 死后的在这些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患者可能会表现出痴呆症状，如 如记忆丧失，混乱，焦虑，抑郁和侵略，这通常出现年或十年（S） 在神经创伤发生后。有待检验的中心假设是，慢性认知和 重复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，拟议的工作不仅使我们能够检验这一假设， 也使我们能够验证新的CTE生物标志物测试以及检查新的Tau，TDP-43 基于蛋白质病的免疫治疗策略，以改善慢性神经行为缺陷。三 在本申请中提出了具体的目的以解决中心假设。具体目标1： 使野生型小鼠经受重复闭合性头部损伤（rCHI）并从亚急性期到慢性期（up 至18个月）描述认知和神经行为变化、整体神经病理学及其相关性 具有脑中时间依赖性CTE样Tau/P-tau和TDP-43蛋白积聚/蛋白质病特征 组织和生物流体。在具体目标2中，我们将使人-tau（hTau）转基因小鼠和TDP-43 过表达rCHI的转基因小鼠，并从亚急性到慢性期跟踪它们，以检查它们是否 出现恶化的认知和神经行为变化，神经病理学和加速，夸大 脑组织和生物流体中的Tau/TDP-43蛋白质病特征。最后，在具体目标3中，我们将结合联合收割机， 从目标1和2中的rCHI模型学习，以测试Tau/P-Tau和TDP-43免疫的潜在作用， 用于降低rCHI-induced Tau和TDP-43蛋白质病负荷和减轻慢性 野生型、hTau、TDP-43转基因和/或 hTau/TDP-43双转基因小鼠系。这项系统性研究将促进我们对 神经行为（焦虑、抑郁、认知功能障碍）及其与 - 易于聚集的蛋白质如Tau和TDP-43（蛋白质病）和CTE的生物化学/蛋白质变化， 就像创伤性脑损伤慢性期的神经退行性级联反应。这些知识可以转化为能力， 为退伍军人管理局设计更好的管理工具和改善退伍军人病人护理。我们的发现也将帮助我们 更好地诊断慢性TBI，包括超灵敏的基于生物流体的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的和有前途的免疫策略来治疗这种疾病。 条件总的来说，这些都是与研究使命一致的重大生物医学进步 符合NF/SG VHS和VA的要求，并符合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临床研究， TBI后发生CTE的风险。

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.