The Effect of Traumatic Brain Injury on Tau Pathology by a Potential Seeding Mechanism

创伤性脑损伤通过潜在播种机制对 Tau 病理学的影响

• 批准号: 9401978
• 负责人: George Allen Edwards III
• 金额: $ 3.1万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-30 至 2019-08-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9401978
• 关键词: Advocate; Affect; Age; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Anatomy; Antibodies; Attenuated; Behavior; Behavioral; Biochemical; Biochemistry; Biological; Biological Assay; Brain; Brain Concussion; Brain Diseases; Brain Pathology; Cell Nucleus; Cerebrospinal Fluid; Clinical; Cognitive; Deposition; Detection; Development; Diagnostic; Diagnostic Procedure; Diagnostic tests; Disease; Early Diagnosis; Emotional; Etiology; Event; Exhibits; Filament; Future; Generations; Histology; Human; Impaired cognition; In Vitro; Individual; Injectable; Kinetics; Knowledge; Laboratories; Lead; Length; Link; Liquid substance; Military Personnel; Mission; Modeling; Molecular; Molecular Conformation; Mus; Nerve Degeneration; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurofibrillary Tangles; Onset of illness; Pathologic; Pathology; Phase; Plasma; Process; Property; Proteins; Public Health; Reaction; Recruitment Activity; Research; Role; Science; Seeds; Services; Severities; Sports; Symptoms; Tauopathies; Techniques; Technology; Testing; Therapeutic; Time; Transgenic Mice; Traumatic Brain Injury; Traumatic injury; United States National Institutes of Health; age related; alpha synuclein; amyloid formation; chronic traumatic encephalopathy; experimental study; head impact; in vivo; mild traumatic brain injury; neurobehavioral; novel; planetary Atmosphere; polymerization; prospective; protein aggregate; protein aggregation; protein misfolding; protein misfolding cyclic amplification; tau Proteins; tau aggregation; tool; translational approach

Project Summary Mild traumatic brain injury is the most common form of impact and is prevalent among contact sports athletes and military personnel. Repetitive mild traumatic brain injury (rmTBI) can generate several molecular cascades that lead to neuropathological consequences in the brain. Moreover, rmTBI has been correlated to neurodegenerative diseases such as chronic traumatic encephalopathy (CTE). CTE is a slow, progressive tauopathy that exhibits neurofibrillary tangles (NFTs) in brain accompanied by psychiatric and cognitive manifestations. NFTs are aggregates formed from the misfolding and aggregation process of tau protein and are canonical in tauopathies such as CTE and Alzheimer’s disease (AD), among others. Individuals following a TBI event can demonstrate early tau accumulation, independent of age, suggesting a potential pathological link between TBI and disease. Formation of amyloids, such as NFTs from tau, is proposed to follow a nucleation-polymerization model where a misfolded seed can trigger native proteins to misfold and aggregate. Introducing a pre-formed seed can accelerate this reaction. The development of tau inclusions and effect on clinical symptoms in connection to rmTBI remain to be elucidated; moreover, effective diagnostic methods for TBI and tau pathology are lacking. This proposal aims to determine the effect of rmTBI on tau pathology along with psychiatric and cognitive sequelae and exploit this misfolded tau for diagnostic assessment in brain and biological fluids by a novel, sensitive assay called tau-protein misfolding cyclic amplification (PMCA). These experiments intend to explore the role of rmTBI, mimicking sub-concussive impacts in athletes, in vivo in contributing to tau pathology and determine if early formed rmTBI-induced tau aggregates have seeding capabilities. Tau-PMCA will be utilized to detect the initiation of tau seeds in brain and biological fluids, such as cerebrospinal fluid (CSF) and blood plasma, triggered by rmTBI in mice as well as connecting the neurobehavioral changes over time. Finally, in a translational approach, tau-PMCA will be used to determine the formation of the first tau seeds in CSF and blood plasma from TBI and AD cases as a diagnostic tool. This proposal conveys the mission of the NIH by advancing science and advocating the establishment of a promising diagnostic strategy. Overall, this proposal will ameliorate the understanding of rmTBI in relation to tau pathology and behavior and potentially detecting disease onset for therapeutic strategies in the future.

项目概要 轻度创伤性脑损伤是最常见的撞击形式，在接触中普遍存在 体育运动员和军事人员可产生重复性轻度创伤性脑损伤 (rmTBI)。 导致大脑神经病理学后果的几种分子级联反应。 rmTBI 与慢性创伤性神经退行性疾病相关 脑病 (CTE) 是一种缓慢、进行性的 tau 蛋白病，表现为神经原纤维缠结。 大脑中伴随精神和认知表现的 NFT 是聚合体。 由 tau 蛋白的错误折叠和聚集过程形成，在 tau蛋白病，例如 CTE 和阿尔茨海默病 (AD) 等。 TBI 事件可以证明早期 tau 积累，与年龄无关，这表明潜在的 TBI 与疾病之间的病理联系是淀粉样蛋白（例如 tau 蛋白的 NFT）的形成。 建议遵循成核聚合模型，其中错误折叠的种子可以触发天然 引入预先形成的种子可以加速这种反应。 与 rmTBI 相关的 tau 包涵体的发展及其对临床症状的影响仍然存在 此外，还缺乏针对 TBI 和 tau 病理学的有效诊断方法。 该提案旨在确定 rmTBI 对 tau 病理学以及精神和疾病的影响 认知后遗症并利用这种错误折叠的 tau 蛋白进行大脑和生物的诊断评估 通过一种名为 tau 蛋白错误折叠循环扩增 (PMCA) 的新颖、灵敏的检测方法对液体进行检测。 实验旨在探索 rmTBI 的作用，模拟运动员的亚震荡影响， 体内对 tau 病理学的影响并确定是否早期形成 rmTBI 诱导的 tau 聚集体 具有播种能力的 Tau-PMCA 将用于检测大脑中 tau 种子的启动。 rmTBI 引发的生物体液，例如脑脊液 (CSF) 和血浆 小鼠以及随着时间的推移连接神经行为变化最后，在转化中。 方法，tau-PMCA 将用于确定 CSF 中第一个 tau 种子的形成， 该提案传达了来自 TBI 和 AD 病例的血浆作为诊断工具的使命。 NIH 通过推进科学发展和倡导建立有前途的诊断方法 总体而言，该提案将增进对 rmTBI 与 tau 相关的理解。 病理和行为，并可能检测疾病发作以制定治疗策略 未来。