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

创伤性脑损伤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。归来退伍军人临床随访的累积证据 患痴呆症和认知功能减退的风险至少是配对患者的2-4倍 非TBI退伍军人。目前对脑外伤后痴呆症的干预措施是有限的，有 目前还没有显示出可以预防、阻止或逆转认知能力下降的干预措施 经历过轻微或严重脑外伤的退伍军人。来自脑外伤动物模型的数据 提示神经炎性反应在介导病理性神经变性中的作用 脑损伤后，但神经炎性反应的特点，无论是在空间上，在大脑和 在时间上与慢性脑损伤认知障碍的关系，还没有被探索。在这方面， 我们已经证明，在小鼠的脑外伤后，观察到了强烈的神经炎性反应 伤后至少6个月。我们还表明，补语系统是一个突出的 触发创伤性脑损伤后的这种神经炎性反应。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，发生和 脑外伤后脑内持续存在，导致原发性脑损伤的代偿机制失效 大脑的认知中枢导致早发性神经变性，这种变性在 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.