The role of complement in chronic neuroinflammation and cognitive decline after closed head brain injury

补体在闭合性脑损伤后慢性神经炎症和认知能力下降中的作用

• 批准号: 10641096
• 负责人: Stephen Tomlinson
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 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 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641096
• 关键词: 3xTg-AD mouse; AD transgenic mice; Acceleration; Address; Adult; Affect; Affective; Age; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Anatomy; Animal Model; Behavioral; Brain; Brain Injuries; CD11c Antigens; Cause of Death; Cells; Cerebrum; Characteristics; Chronic; Chronic Phase; Clinical; Closed head injuries; Cognitive; Cognitive deficits; Complement; Complement 3d Receptors; Complement Activation; Data; Dementia; Disease; Environmental Risk Factor; Event; Failure; Female; Genetic Transcription; Goals; Growth Factor; Head; ITGAM gene; ITGB2 gene; Immunologics; Impaired cognition; Impairment; Infiltration; Injury; Internal Ribosome Entry Site; Intervention; Knockout Mice; Knowledge; Limbic System; Link; Longitudinal Studies; Macrophage-1 Antigen; Magnetic Resonance Imaging; Measures; Mediating; Microglia; Military Personnel; Modeling; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neuronal Plasticity; Neurons; Outcome; Pathologic; Pathology; Performance; Phagocytosis; Population; Process; Production; Reporter; Risk Factors; Role; Schedule; Serum; Signal Transduction; Site; Source; Synapses; Synaptic plasticity; System; Tauopathies; Testing; Therapeutic; Tomatoes; Transgenic Mice; Traumatic Brain Injury; Treatment Protocols; Veterans; Wild Type Mouse; Work; animal data; behavioral outcome; burden of illness; clinically relevant; complement system; dementia risk; disability; early onset; executive function; experience; follow-up; high risk; hyperphosphorylated tau; imaging study; improved; inhibitor; long-term sequelae; male; mouse model; neurobehavioral; neurobehavioral test; neuroinflammation; post intervention; prevent; receptor; response; tau aggregation; translational approach; treatment strategy

Traumatic brain injury (TBI) is a major risk factor for early-onset dementia and Alzheimer’s Disease among Veterans. Cumulative evidence from clinical follow-up of returning Veterans demonstrate at least 2-4 times higher risk of dementia and cognitive decline compared to matched non-TBI Veterans. The current interventions for post-TBI dementia are limited, and there are currently no interventions that have shown to prevent, stop, or reverse cognitive decline in Veterans who have experienced either mild or severe TBI. Data from animal models of TBI indicate a role for the neuroinflammatory response in mediating pathological neurodegeneration after TBI, but characteristics of the neuroinflammatory response, both spatially in the brain and temporally in relation to cognitive deficits in chronic TBI, has not been explored. In this context, we have shown that following TBI in mice, there is a robust neuroinflammatory which is observed at least 6 months after TBI. We have also shown that the complement system is a prominent trigger of this neuroinflammatory response after TBI. In this project, we propose to investigate the hypothesis that post-traumatic complement activation and neuroinflammation, that occurs and persists in the brain following TBI, leads to failure of compensatory mechanisms in primary cognitive centers of the brain leading to early onset neurodegeneration that is accelerated in an Alzheimer’s disease mouse model.

创伤性脑损伤（TBI）是早发性痴呆和阿尔茨海默氏症的主要危险因素 退伍军人中的疾病来自对返回退伍军人的临床随访的累积证据。 与匹配的人相比，患痴呆症和认知能力下降的风险至少高 2-4 倍 非 TBI 退伍军人目前对 TBI 后痴呆的干预措施有限，而且有多种方法。 目前尚无干预措施能够预防、阻止或逆转认知能力下降 经历过轻度或重度 TBI 的退伍军人 来自 TBI 动物模型的数据。 表明神经炎症反应在介导病理性神经变性中的作用 TBI 后，但神经炎症反应的特征，无论是在大脑的空间上还是在 在这方面，尚未探讨与慢性 TBI 认知缺陷的时间关系。 我们已经证明，在小鼠 TBI 后，观察到存在强烈的神经炎症 TBI 后至少 6 个月我们还表明补体系统是一个突出的。 TBI 后触发这种神经炎症反应的因素。 假设创伤后补体激活和神经炎症发生 TBI 后大脑中持续存在，导致原发性代偿机制失效 大脑的认知中心导致早发性神经退行性变，这种退行性病变会加速 阿尔茨海默病小鼠模型。