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

创伤性脑损伤（TBI）是早发性痴呆和阿尔茨海默病的主要危险因素 退伍军人中的疾病退伍军人临床随访的累积证据 痴呆和认知能力下降的风险至少比匹配的高2-4倍 非TBI退伍军人目前对TBI后痴呆的干预是有限的， 目前还没有干预措施显示可以预防，停止或逆转认知能力下降， 经历过轻度或重度TBI的退伍军人。TBI动物模型数据 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，无论是在空间上在大脑中， 在时间上与慢性TBI中认知缺陷的关系尚未探索。在这一背景下， 我们已经表明，在小鼠TBI后，观察到强烈的神经炎症， 至少6个月。我们还表明，补体系统是一个突出的 TBI后神经炎症反应的触发因素。在这个项目中，我们建议调查 假设创伤后补体激活和神经炎症，发生， 持续存在于脑外伤后，导致代偿机制的失败，在原发性 大脑的认知中心，导致早发性神经退行性变， 阿尔茨海默病小鼠模型。

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.