Project Summary/Abstract Traumatic brain injury (TBI) has emerged as a leading cause of death and disability. It results in a heightened risk for long-term disease sequelae including Alzheimer’s disease (AD) and chronic traumatic encephalopathy. Despite being a growing medical issue, the biological factors that promote central nervous system (CNS) pathology and neurological dysfunction following TBI remain poorly characterized. Recently, the CNS lymphatic system was identified as a critical mediator of drainage from the CNS to the periphery. In comparison to other peripheral organs, our understanding of how defects in lymphatic drainage from the CNS contribute to disease is limited. It is still unknown how TBI impacts CNS lymphatic function and whether disruptions in this drainage pathway are involved in driving TBI pathogenesis. In preliminary studies, I found that even mild forms of brain trauma cause severe deficits in CNS lymphatic drainage that can last out to at least two weeks post- injury. Moreover, I observed that pre-existing CNS lymphatic dysfunction mediated by targeted photoablation before TBI leads to increased neuroinflammation and cognitive deficits. Given these preliminary findings, I hypothesize that CNS lymphatic dysfunction contributes to TBI pathogenesis by promoting sustained inflammation in the brain and that impairments in this lymphatic system contribute to amyloid beta (Aβ) build-up in mouse models of AD. In Aim 1, I will use surgical, behavioral and imaging techniques to determine whether pre-existing lymphatic dysfunction contributes to increased inflammation in the brain and adverse long-term behavioral outcomes. In Aim 2, I will utilize lymphatic modulating techniques in a mouse model of AD to assess whether CNS lymphatic dysfunction after TBI results in buildup of Aβ in both the brain and meninges and whether boosting lymphatic function is able to decrease Aβ deposition in the brain. Collectively, this proposal will provide new insights into the consequences of CNS lymphatic dysfunction in TBI, shed light on the mechanisms behind why TBI results in a higher risk for neurodegenerative disease, and offer potential therapeutic options to target the CNS lymphatic system after TBI.