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

创伤后睡眠觉醒中断在轻度创伤性脑损伤后 tau 病理学发展中的作用

• 批准号: 10588916
• 负责人: Jeffrey J Iliff
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588916
• 关键词: Acute; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Amyloid beta-Protein; Anatomy; Behavior assessment; Blood Vessels; Brain; Brain Concussion; Cerebrospinal Fluid; Chronic; Chronic Phase; Clinical; Clinical Research; Deposition; Development; Diagnosis; Dose; Drowsiness; Exhibits; Exposure to; Histologic; Image; Immunofluorescence Immunologic; Immunohistochemistry; Impaired cognition; Impairment; Individual; Injury; Intercellular Fluid; Life; Link; Liquid substance; Magnetic Resonance Imaging; Microdialysis; Military Personnel; Modeling; Mus; Nerve Degeneration; Neurocognitive Deficit; Neurodegenerative Disorders; Neurons; Pathologic; Pathology; Pathway interactions; Pattern; Physiological; Play; Population; Post-Concussion Syndrome; Prevention; Process; Proteins; Recording of previous events; Reporting; Risk Factors; Rodent Model; Role; Sampling; Senile Plaques; Sleep; Sleep Deprivation; Sleep Wake Cycle; Sleep disturbances; Slice; System; Tauopathies; Techniques; Testing; Time; Transgenic Organisms; Translational Research; Traumatic Brain Injury; Veterans; Wild Type Mouse; aging brain; brain cell; brain dysfunction; central nervous system injury; chronic traumatic encephalopathy; clinical risk; demented; dementia risk; epidemiology study; functional decline; functional disability; genetic approach; glymphatic clearance; glymphatic dysfunction; glymphatic function; glymphatic system; human subject; improved; in vivo; injured; interstitial; mild traumatic brain injury; military veteran; mouse model; novel; novel strategies; pharmacologic; prevent; protein aggregation; response; service member; tau Proteins; tau aggregation; tau-1; wasting

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.

项目概要 轻度创伤性脑损伤（mTBI、脑震荡）已成为发生以下疾病的危险因素 神经退行性疾病，例如阿尔茨海默病和慢性创伤性脑病， 其特征是神经细胞内 tau 蛋白的异常聚集。然而，将 mTBI 与 tau蛋白在生命后期的病理学仍然未知。 类淋巴系统是最近表征的全脑血管周围空间网络，支持 脑脊液和间质液的快速交换。类淋巴功能有助于清除两者 β 淀粉样蛋白和 tau 淀粉样蛋白的损伤被认为是它们在衰老大脑中沉积的基础。淋巴管 通路功能在睡眠期间最强，并且会因创伤性脑损伤而受损。基于这些发现， 我们假设 mTBI 后类淋巴功能受损会减慢 tau 的清除， 有助于损伤后 tau 病理学的发展。使用完善的重复模型 原始 mTBI、认知和功能障碍的行为评估以及 tau 蛋白的组织学评估 在 tau 蛋白病啮齿动物模型的病理学中，我们将描述急变 mTBI 后的类淋巴功能障碍， 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 老龄化人群中阿尔茨海默病等疾病的发展。最近的临床和 转化研究表明，SWD 实际上可能促进阿尔茨海默病相关疾病的发展 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。使用上面的并行技术，我们将定义爆炸 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表现 单次或重复 mTBI 后的时间分布。全面定义类淋巴系统的作用 损伤和睡眠中断在 mTBI 后 tau 病理学的发展中发挥作用，这些研究将 在单次和重复的 mTBI 小鼠模型中并行进行。 这项研究的结果可能为研究发展的机制提供一个新的视角。 创伤后神经变性，并可能支持针对类淋巴通路功能和 SWD 预防和治疗有退伍军人病史的退伍军人群体中的阿尔茨海默病等疾病 暴露于 mTBI。