Role of complement in TBI

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Traumatic brain injury (TBI) is a major risk factor for developing neurological disorders. 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 therapies that have shown to prevent, stop, or reverse cognitive decline in patients who have experienced either mild or severe TBI. There is increasing evidence that a chronic neuroimmune/inflammatory response induced by TBI plays a central role in the pathophysiology of neurodegenerative disorders. However, this response can vary greatly between different types of brain injury and can vary at different stages after injury. We propose to investigate the neuroimmune/inflammatory response that occurs and develops chronically after severe focal contusion injury vs. mild diffuse concussive injury. The complement system is a key mediator of inflammation, and the focus of this proposal is the role of complement in chronic neuroimmune responses and neurodegeneration that occurs after these different types of brain insults. Understanding differences in post-TBI neuroimmune responses, as well as regional differences, will permit the design of appropriately tailored therapies, including complement inhibitory therapies, according to the type and stage of injury. Overall, the aims of this proposal are to investigate the role of complement in pathophysiological regional responses after contusion versus concussive injuries, to compare neurobehavioral outcomes after contusion versus concussive injuries and determine associations with post-traumatic neuroinflammation and pathology, and finally to investigate the role of CNS derived complement vs. peripheral complement, as well as immune cell complement receptors in chronic pathology after either contusion or concussive injuries.