CTBI: Tauopathy in mice and human: Surrogate Plasma Biomarkers for Brain Trauma-Initiated Neurodegenerative Disease

摘要/项目摘要 关联VA优点整体研究策略：开阔场地爆炸或重复轻度爆炸造成的创伤性脑损伤(TBI) 对人类tau转基因小鼠(Htau)的影响将诱导阿尔茨海默病相关的tau依赖的病理 抑制tau或用阻断tau聚集的治疗药物治疗。颅脑损伤诱导的tau相关超微结构 将分析暴露在冲击波中的小鼠和退伍军人的大脑变化，以及血浆生物标记物 脑外伤和/或阿尔茨海默病-病理学将在小鼠身上确认，并在人类身上得到验证。 脑外伤是退伍军人中普遍存在的危险因素，增加了神经退行性疾病的风险，如后遗症 外伤性癫痫、帕金森氏症和神经官能症[慢性创伤性脑病和阿尔茨海默病 疾病(AD)]。尽管数百万人处于危险之中，但缺乏敏感和实用的血液生物标记物来预测 不利的长期结果并跟踪疾病进展，以监测干预措施的有效性 前驱期延长。这项提议的首要目标是填补这一知识空白。 初步数据显示，与脑损伤相关的神经退行性变和神经炎症是tau依赖的。 星形胶质细胞中神经炎性蛋白GFAP和AQP4的水平与疾病严重程度密切相关 在脑外伤受试者的大脑中(链接PI：McKee)。此外，我们在htau小鼠和人类身上的数据支持 假设这些蛋白在血浆细胞外小泡(EVS)中的水平与脑病理平行。也是 数据表明，从大脑分离的EVS含有ptau(寡聚体和碎片)和树突状细胞的标记。 和轴突变性(神经颗粒素、SNAP-25、神经细丝)和血浆EVS水平。最后，我们展示了 在htau小鼠中，一种致病tau聚集的鼻腔给药抑制剂减少了CNS tau在 Htau老鼠。 在目标1中，我们建议使用我们的重复轻度脑损伤(RmTBI)模型来检验血浆EV 表位随着时间的推移而演变，反映了神经胶质反应、神经退行性变和肌萎缩症。在目标2中，我们验证了 生物标志物的准确性，检验以下假设：(A)特定的tau聚集体促进持久性 脑损伤中与EV生物标志物相对应的胶质增生和变性，以及(B)相反，tau的调节 使用tau聚集抑制剂的聚集，减少tau寡聚体、胶质增生和tau病，类似地影响 EV生物标志物。我们的血浆样本随后被(链接项目：夏博士)用来更充分地利用蛋白质组学 脑创伤后EV中tau改变的特征及其他脑持续EV生物标志物的鉴定 神经退行性变和紧张症。目标3寻求使用组织来扩展我们的EV生物标记物方法(链接 项目：Gu博士)，来自与老兵模型相同的受冲击伤的转基因或不转基因小鼠 暴露并导致神经退化。这一目标还包括对人体血浆的评估(和共享 来自所有四个VA部位的AD、MCI或TBI患者。总的来说，这些研究应该会产生强有力的 候选替代血液生物标记物，为了解导致致病事件的新的和可访问的窗口 致CTE和AD。这种类型的替代血液生物标记物应该能够促进CTE治疗的发展 和AD，并对退伍军人的长期健康和相关成本有很大影响。

ABSTRACT/PROJECT SUMMARY Linked VA Merit Overall Research Strategy: Traumatic brain injury (TBI) from Open Field Blast or repeat mild impact to human tau transgenic mice (htau) will induce Alzheimer-relevant, tau-dependent pathology rescued by tau suppression or treated with therapeutics that block tau aggregation. TBI-induced tau-related ultrastructural changes will be analyzed in brains from both mice and Veterans exposed to blast, and plasma biomarkers for TBI and/or Alzheimer-pathology will be identified in mice and validated in humans. TBI is a risk factor prevalent in Veterans, increasing the risk for neurodegenerative diseases such as post- traumatic epilepsy, Parkinson’s and tauopathies [chronic traumatic encephalopathy (CTE) and Alzheimer disease (AD)]. Despite millions at risk, there is a paucity of sensitive and practical blood biomarkers that predict adverse long-term outcomes and track disease progression to monitor efficacy of interventions during the extended prodromal period. The overarching goal of this proposal is to fill this knowledge gap. Preliminary data show that TBI-associated neurodegeneration and neuroinflammation are tau-dependent. The levels of the neuroinflammatory proteins GFAP and AQP4 in astrocytes robustly parallels disease severity in the brains of TBI subjects (linked PI: McKee). Further, our data in htau mice and humans, support the hypothesis that the level of these proteins in plasma extracellular vesicles (EVs) parallel brain pathology. Also data suggest that EVs isolated from the brain contain ptau (oligomers and fragments) and markers of dendritic and axonal degeneration (neurogranin, SNAP-25, neurofilaments) and levels plasma EVs. Finally, we show that in htau mice, an intranasally delivered inhibitor of pathogenic tau aggregation reduces CNS tau accumulation in htau mice. In Aim 1 we propose to use our repetitive mild TBI (rmTBI) model to test the hypothesis that plasma EV epitopes evolve over time and reflect glial responses, neurodegeneration and tauopathy. In Aim 2 we validate the accuracy of the biomarkers, testing the hypotheses that (A) specific tau aggregates promote persistent gliosis and degeneration in TBI corresponding to the EV biomarkers , and (B) conversely, that modulation of tau aggregation with a tau aggregation inhibitor, reduces tau oligomers, gliosis and tauopathy, similarly affecting the EV biomarkers. Our plasma samples are then used by (linked project: Dr. Xia) to use proteomics to more fully characterize altered tau in brain EVs post TBI and to identify other persistent brain EV biomarkers for post-TBI neurodegeneration and tauopathy. Aim 3 seeks to extend our EV biomarker approach using tissue (linked project: Dr. Gu), from the same mice with or without the transgene exposed to blast injury that models Veteran exposure and drives neurodegeneration. This aim also includes the evaluation (and sharing) of human plasma from patients with AD, MCI or TBI from all four VA sites. Collectively these studies should produce strong candidate surrogate blood biomarkers, offering a new and accessible window to the pathogenic events leading to CTE and AD. This type of surrogate blood biomarker should enable the development of treatments for CTE and AD and have a high impact on long-term Veteran health and related costs.