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

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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.