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.

项目摘要 轻度创伤性脑损伤（MTBI，脑震荡）已成为发展的危险因素 神经退行性疾病，例如阿尔茨海默氏病和慢性创伤性脑病，是 以神经细胞内tau的异常聚集为特征。但是，将mtbi连接到的机制 后来生活中的tau病理仍然未知。 Glymphatic系统是最近表征的脑血管周空间网络，支持该网络 快速交换脑脊液和间质液。胶状功能有助于清除两者 淀粉样蛋白β和Tau及其损害被认为是它们在衰老大脑中的沉积基础。胶状 途径功能在睡眠期间最大，并且受到创伤性脑损伤的损害。基于这些发现， 我们假设MTBI后的Glymphatic功能的损害减慢了Tau和 受伤后有助于tau病理的发展。使用重复的良好模型 爆炸MTBI，认知和功能障碍的行为评估以及TAU的组织学评估 在啮齿动物模型的啮齿动物模型中，我们将表征爆炸MTBI之后的淋巴功能障碍， 并测试其损害是否促进创伤后的双胞胎病。 MTBI之后，睡眠觉醒周期的破坏（SWD）是经常出现的慢性投诉。 SWD也随附 衰老人口中阿尔茨海默氏病等疾病的发展。最近的临床和 翻译研究表明，SWD实际上可能促进了与阿尔茨海默氏症相关的发展 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之后的tauopathy。使用上面的平行技术，我们将在Blast MTBI之后定义SWD，然后测试 创伤后SWD是否促进受伤后TAU病理的发展。 在观察性临床研究和啮齿动物模型中，脑震荡症状均表现出不同 单一或重复MTBI之后的时间曲线。全面定义胶状的作用 MTBI后TAU病理发展的障碍和睡眠中断发挥作用，这些研究将是 在单一和重复的爆炸MTBI的小鼠模型中并行进行。 这项研究的结果可能提供了关于开发机制的新观点 创伤后神经变性，并可能支持靶向牙性途径功能和SWD的靶向 预防和治疗诸如阿尔茨海默氏病的疾病中 接触MTBI。