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

CTBI：小鼠和人类的 Tau 蛋白病：脑外伤引发的神经退行性疾病的替代血浆生物标志物

• 批准号: 10292944
• 负责人: GREGORY M COLE
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292944
• 关键词: Acute; Address; Affect; Aftercare; Age; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Astrocytes; Behavior; Biological Markers; Blast Injuries; Blood; Brain; Brain Concussion; Brain Pathology; Cause of Death; Cerebrovascular system; Chronic; Collection; Craniocerebral Trauma; Data; Deposition; Devices; Diagnostic; Disease; Disease Progression; Edema; Encephalitis; Epitopes; Evaluation; Event; Exposure to; Glial Fibrillary Acidic Protein; Gliosis; Goals; Health; Human; Injury; Knowledge; Life; Link; Membrane; Memory Loss; Methods; Modeling; Modification; Monitor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Outcome; Parkinson Disease; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Plasma; Post-Translational Protein Processing; Post-Traumatic Epilepsy; Preparation; Proteins; Proteomics; Research; Risk; Risk Factors; Role; S-nitro-N-acetylpenicillamine; Sampling; Services; Severity of illness; Site; Source; Surrogate Markers; Survivors; Synapses; Tauopathies; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Transgenes; Transgenic Mice; Translations; Traumatic Brain Injury; Treatment Efficacy; Validation; Veterans; aquaporin 4; axonal degeneration; behavioral phenotyping; biomarker performance; chronic traumatic encephalopathy; cost; endoplasmic reticulum stress; exosome; extracellular; extracellular vesicles; feasibility testing; glial activation; glymphatic system; head impact; inhibitor; innovation; insight; long-term sequelae; mild traumatic brain injury; monomer; neural circuit; neurofilament; neurogranin; neuroinflammation; neuropathology; novel; predictive marker; preservation; rational design; response; specific biomarkers; tau Proteins; tau aggregation; tau expression; tau mutation; tau-1; therapy development; vesicular release; water channel

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.

摘要/项目摘要 关联 VA 优异总体研究策略：露天爆炸或重复轻度创伤性脑损伤 (TBI) 对人类 tau 转基因小鼠 (htau) 的影响将诱发与阿尔茨海默病相关的 tau 依赖性病理 tau 抑制或采用阻断 TBI 诱导的 tau 相关超微结构的治疗方法进行治疗。 将分析暴露于爆炸的小鼠和退伍军人的大脑中的变化，以及血浆生物标志物 TBI 和/或阿尔茨海默病病理学将在小鼠中进行鉴定，并在人类中进行验证。 TBI 是退伍军人中普遍存在的危险因素，会增加神经退行性疾病的风险，例如后遗症。 创伤性癫痫、帕金森病和 tau 病 [慢性创伤性脑病 (CTE) 和阿尔茨海默病 尽管有数百万人面临风险，但仍缺乏敏感且实用的血液生物标志物来预测。 不良的长期结果并跟踪疾病进展，以监测治疗期间干预措施的效果 该提案的总体目标是填补这一知识空白。 初步数据表明，TBI 相关的神经变性和神经炎症是 tau 依赖性的。 星形胶质细胞中神经炎症蛋白 GFAP 和 AQP4 的水平与疾病严重程度密切相关 此外，我们在 htau 小鼠和人类中的数据支持了 TBI 受试者的大脑。 假设血浆细胞外囊泡（EV）中这些蛋白质的水平与大脑病理学平行。 数据表明，从大脑中分离出的 EV 含有 ptau（寡聚物和片段）和树突标记物 和轴突变性（神经粒蛋白、SNAP-25、神经丝）和血浆 EV 水平最后，我们证明了这一点。 在 htau 小鼠中，鼻内递送的致病性 tau 聚集抑制剂可减少中枢神经系统 tau 的积累 htau 小鼠。 在目标 1 中，我们建议使用我们的重复轻度 TBI (rmTBI) 模型来检验血浆 EV 的假设 表位随时间演变并反映神经胶质反应、神经变性和 tau 蛋白病。在目标 2 中，我们验证了这一点。 生物标志物的准确性，测试 (A) 特定 tau 聚集体促进持久性的假设 TBI 中的神经胶质增生和变性对应于 EV 生物标志物，并且 (B) 相反，tau 的调节 与 tau 聚集抑制剂聚集，减少 tau 寡聚体、神经胶质增生和 tau 病，同样影响 然后，我们的血浆样本被（相关项目：夏博士）用来更充分地利用蛋白质组学。 表征 TBI 后脑部 EV 中 tau 蛋白的改变，并确定 TBI 后其他持久性脑部 EV 生物标志物 目标 3 寻求使用组织（相关联）扩展我们的 EV 生物标志物方法。 项目：Gu 博士），来自暴露于爆炸损伤的转基因小鼠，模拟退伍军人 该目标还包括对人类血浆的评估（和共享）。 总的来说，这些研究应该产生强有力的结果。 候选替代血液生物标志物，为主要致病事件提供了一个新的、可访问的窗口 这种类型的替代血液生物标志物应该能够促进 CTE 治疗方法的开发。 和 AD，并对退伍军人的长期健康和相关成本产生重大影响。