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.

项目摘要 轻度创伤性脑损伤是影响的最常见形式，在接触中很普遍 体育运动员和军事人员。重复的轻度外伤性脑损伤（RMTBI）可以产生 几种分子级联反应会导致大脑神经病理学后果。而且， RMTBI与神经退行性疾病（例如慢性创伤性）相关 脑病（CTE）。 CTE是一种缓慢的进行性tauopathy，表现出神经纤维缠结 （NFT）在由精神病和认知表现管理的大脑中。 NFT是骨料 由tau蛋白的错误折叠和聚集过程形成，在 诸如CTE和阿尔茨海默氏病（AD）之类的tauopathies。遵循的个人 TBI事件可以证明早期的tau积累，与年龄无关，表明潜力 TBI与疾病之间的病理联系。淀粉样蛋白的形成，例如tau的NFT，是 提议遵循成核聚合模型，其中错误折叠的种子可以触发天然 蛋白质不折叠和聚集。引入预成型种子可以加速这种反应。 与RMTBI有关的tau包含物的发展以及对临床症状的影响 阐明；此外，缺乏有效的TBI和TAU病理学诊断方法。 该建议旨在确定rmtbi对tau病理的影响以及精神科和 认知后遗症并利用这种错误折叠的tau进行脑和生物学的诊断评估 通过一种称为tau蛋白质折叠循环扩增（PMCA）的新型，敏感测定的流体。这些 实验打算探索rmtbi的作用，模仿运动员的亚置影响 体内有助于tau病理学并确定早期形成rmtbi诱导的tau聚集体 具有播种能力。 tau-pmca将用于检测大脑中tau种子的主动性 和生物流体，例如脑脊液（CSF）和血浆，由RMTBI触发 随着时间的流逝，小鼠以及连接神经行为的变化。最后，在翻译中 方法，Tau-PMCA将用于确定CSF中第一个Tau种子的形成 TBI和AD病例的血浆作为诊断工具。该提议传达了 NIH通过推进科学并主张建立有前途的诊断 战略。总体而言，该提案将改善对RMTBI的理解 病理和行为，并可能检测疾病发作以进行治疗策略 未来。