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.

项目总结 轻度创伤性脑损伤(mTBI，脑震荡)已成为发展为 神经退行性疾病，如阿尔茨海默病和慢性创伤性脑病，它们是 以神经细胞内tau的异常聚集为特征。然而，将mTBI与 在生命的后期，tau的病理仍未可知。 淋巴系统是最近表征的全脑血管周围空间网络，它支持 脑脊液和间质液体快速交换。淋巴功能有助于两者的清除 淀粉样β蛋白和tau蛋白及其损伤被认为是它们在老化的大脑中沉积的基础。语调的 通路功能在睡眠时最强，并受到创伤性脑损伤的损害。基于这些发现， 我们假设mTBI后淋巴功能的损害减缓了tau和tau的清除。 有助于损伤后tau病理的发展。利用一个公认的重复模型-- BLAST mTBI、认知和功能损害的行为评估以及tau的组织学评估 在一种变态反应的啮齿动物模型中，我们将表征冲击性mTBI后的淋巴功能障碍， 并测试它的损伤是否会促进创伤后直肌失调。 睡眠-觉醒周期(SWD)的中断是mTBI后常见的慢性主诉。社署亦有陪同人员 老年痴呆症等疾病在老龄化人口中的发展。最近的临床和 翻译研究表明，社保实际上可能促进阿尔茨海默氏症相关疾病的发展 病理学，包括Tau的沉积。基于mTBI、SWD和MTI之间的常见临床联系 神经退行性疾病，我们假设创伤后的SWD有助于 颅脑损伤后的肌张力障碍。使用上面的并行技术，我们将在BLAST mTBI之后定义SWD，并进行测试 创伤后SWD是否促进了创伤后tau病理的发展。 在观察性临床研究和啮齿动物模型中，脑震荡后症状表现出不同 单次或重复mTBI后的时间分布。全面定义歌舞演员的角色 损伤和睡眠障碍在mTBI后tau病理的发展中起作用，这些研究将是 在单次冲击波和重复冲击波mTBI小鼠模型中并行进行。 这项研究的结果可能为研究糖尿病发生的机制提供了一个新的视角。 创伤后神经变性，并可能支持靶向淋巴通路功能和SWD在 在有老年痴呆症病史的退伍军人中预防和治疗阿尔茨海默病等疾病 暴露于mTBI。