The role of post-traumatic sleep-wake disruption in the development of tau pathology following mild traumatic brain injury

项目摘要 轻度创伤性脑损伤（mTBI，脑震荡）已成为发展的风险因素， 神经退行性疾病，如阿尔茨海默病和慢性创伤性脑病， 其特征在于神经细胞内tau蛋白的异常聚集。然而，将mTBI与 tau病理学在以后的生活中仍然未知。 胶质淋巴系统是最近表征的血管周围空间的全脑网络，其支持神经系统的功能。 脑脊液和间质液的快速交换。淋巴功能有助于清除这两种 淀粉样蛋白β和tau，并且其损伤被认为是它们在老化大脑中沉积的基础。胶质淋巴 通路功能在睡眠期间最大，并且受到创伤性脑损伤的损害。根据这些发现， 我们假设mTBI后胶质淋巴功能的损伤减缓了tau蛋白的清除， 有助于损伤后tau病理学的发展。使用一个完善的重复模型- 原始细胞mTBI、认知和功能障碍的行为评估以及tau蛋白的组织学评估 病理学在tau蛋白病的啮齿动物模型中，我们将表征原始细胞mTBI后的胶质淋巴功能障碍， 并测试其损伤是否会促进创伤后tau蛋白病。 睡眠-觉醒周期（SWD）中断是mTBI后常见的慢性主诉。社署亦陪同 老年人中阿尔茨海默病等疾病的发展。最近的临床和 翻译研究表明，SWD实际上可能会促进阿尔茨海默氏症相关疾病的发展， 病理学，包括tau沉积。基于mTBI、SWD和 神经退行性疾病，我们假设创伤后SWD有助于发展 mTBI后的tau蛋白病。使用上述并行技术，我们将定义冲击波mTBI后的SWD，并测试 创伤后SWD是否促进损伤后tau病理学的发展。 在观察性临床研究和啮齿动物模型中，脑震荡后症状表现出不同的 单次或重复mTBI后的时间曲线。为了全面定义胶质淋巴细胞的作用 损伤和睡眠中断在mTBI后tau病理学的发展中起作用，这些研究将 在单次和重复原始mTBI的小鼠模型中平行进行。 本研究的结果可能为研究脑梗死的发生机制提供一个新的视角。 创伤后神经变性，并可能支持靶向胶质淋巴通路功能和SWD在 预防和治疗老年痴呆症等疾病 暴露于mTBI。

PROJECT SUMMARY Mild traumatic brain injury (mTBI, concussion) has emerged as a risk factor for the development of neurodegenerative conditions such as Alzheimer's disease and chronic traumatic encephalopathy, which are characterized by the aberrant aggregation of tau within neural cells. However, the mechanisms linking mTBI to tau pathology later in life remain unknown. The glymphatic system is a recently characterized brain-wide network of perivascular spaces that supports the rapid exchange of cerebrospinal and interstitial fluid. Glymphatic function contributes to the clearance of both amyloid beta and tau, and its impairment is believed to underlie their deposition in the aging brain. Glymphatic pathway function is greatest during sleep and is impaired by traumatic brain injury. Based on these findings, we hypothesize that that impairment of glymphatic function following mTBI slows the clearance of tau and contributes to the development of tau pathology following injury. Using a well-established model of repetitive- blast mTBI, behavioral assessment of cognitive and functional impairment, and histological assessment of tau pathology in a rodent model of tauopathy, we will characterize glymphatic dysfunction following blast mTBI, and test whether its impairment promotes post-traumatic tauopathy. Disruption of the sleep-wake cycle (SWD) is a frequent chronic complaint after mTBI. SWD also accompanies the development of conditions like Alzheimer's disease in aging populations. More recent clinical and translational research suggests that SWD may actually promote the development of Alzheimer's-related pathology, including tau deposition. Based on the common clinical connections between mTBI, SWD, and neurodegenerative disease, we hypothesize that post-traumatic SWD contributes to the development of tauopathy following mTBI. Using parallel techniques above, we will define SWD following blast mTBI, and test whether post-traumatic SWD promotes the development of tau pathology after injury. In both observational clinical studies and in rodent models, post-concussive symptoms exhibit different temporal profiles following single or repetitive mTBI. To comprehensively define the role that glymphatic impairment and sleep disruption play in the development of tau pathology following mTBI, these studies will be carried out in parallel in mouse models of single and repetitive blast mTBI. The results of this study may provide a novel perspective on the mechanisms underlying the development of post-traumatic neurodegeneration, and may support targeting glymphatic pathway function and SWD in the prevention and treatment of conditions such as Alzheimer's disease in Veteran populations with a history of exposure to mTBI.