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: 10044409
• 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/10044409
• 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; design; endoplasmic reticulum stress; exosome; extracellular; extracellular vesicles; feasibility testing; glial activation; glymphatic system; head impact; inhibitor/antagonist; innovation; insight; mild traumatic brain injury; monomer; neural circuit; neurofilament; neurogranin; neuroinflammation; neuropathology; novel; predictive marker; preservation; 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/项目总结 关联VA Merit总体研究策略：开放性爆炸或重复轻度创伤性脑损伤（TBI） 对人tau转基因小鼠（htau）影响将诱导阿尔茨海默病相关的tau依赖性病理学， tau抑制或用阻断tau聚集的治疗剂治疗。TBI诱导的tau相关超微结构 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 TBI和/或阿尔茨海默病将在小鼠中鉴定并在人类中验证。 TBI是退伍军人中普遍存在的风险因素，增加了神经退行性疾病的风险，如术后 创伤性癫痫、帕金森病和tau蛋白病[慢性创伤性脑病（CTE）和阿尔茨海默病 疾病（AD）。尽管有数百万人处于危险之中，但缺乏敏感和实用的血液生物标志物来预测 不良长期结局，并跟踪疾病进展，以监测干预措施在治疗期间的疗效。 前驱期延长。本提案的总体目标是填补这一知识空白。 初步数据显示，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性蛋白GFAP和AQP 4的水平与疾病的严重程度密切相关 在TBI受试者的大脑中（相关PI：McKee）。此外，我们在htau小鼠和人类中的数据支持 假设这些蛋白质在血浆细胞外囊泡（EV）中的水平与脑病理学平行。也 数据表明，从脑中分离的EV含有ptau（寡聚体和片段）和树突状细胞的标记物， 以及轴突变性（神经颗粒蛋白、SNAP-25、神经丝）和血浆EV水平。最后，我们表明， 在htau小鼠中，鼻内递送的致病性tau聚集的抑制剂减少了 htau小鼠。 在目标1中，我们提出使用我们的重复性轻度TBI（rmTBI）模型来检验血浆EV 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 生物标志物的准确性，测试以下假设：（A）特异性tau聚集体促进持续的 对应于EV生物标志物的TBI中的神经胶质增生和变性，和（B）相反，tau的调节 与tau聚集抑制剂一起聚集，减少tau寡聚体、神经胶质增生和tau病变，类似地影响tau蛋白的表达。 EV生物标志物。我们的血浆样本随后被（相关项目：夏博士）用于更全面地使用蛋白质组学， 表征TBI后脑EV中改变的tau，并鉴定TBI后的其他持续性脑EV生物标志物 神经变性和tau蛋白病。目标3寻求使用组织（相关的）扩展我们的EV生物标志物方法。 Gu博士），来自相同的小鼠，有或没有转基因暴露于冲击伤，模型退伍军人 暴露和驱动神经退化。这一目标还包括评估（和共享）人血浆 来自所有四个VA中心的AD、MCI或TBI患者。总的来说，这些研究应该产生强大的 候选替代血液生物标志物，提供了一个新的和可访问的窗口，致病事件导致 CTE和AD。这种类型的替代血液生物标志物应该能够开发CTE的治疗方法 和AD，并对退伍军人的长期健康和相关费用产生很大影响。