Adolescent alcohol exposure exacerbates rmTBI associated BBB disruption and dementia risk

Title: Adolescent alcohol exposure exacerbates rmTBI associated BBB disruption and dementia risk Approximately 20% of adolescents self-report experiencing one or more mild traumatic brain injuries (mTBI) with adolescent athletes being at a higher risk than non-athletic peers. Additionally, rates of alcohol consumption are higher in adolescents participating in team sports. The adolescent brain is especially vulnerable to both insults. Over the years, dementia has been linked to a variety of diseases and injuries, among them alcohol consumption and TBI, with repeat mild TBI (rmTBI) believed to be the primary factor in the development of chronic traumatic encephalopathy (CTE) a neurodegenerative disease that leads to dementia. Dementia is a leading cause of disability and dependency worldwide, with an estimated annual cost of $1.3 trillion (US). One important brain feature that is disrupted by TBI and alcohol, as well as being heavily implicated in the development of dementias, is the blood-brain barrier (BBB). The BBB is an intricately linked cellular and molecular structure that maintains homeostasis in the microenvironment of the brain by regulating the access of blood-borne molecules into the tissues, and critically the BBB plays a role in the production and clearance of amyloid beta. Alcohol has been shown to disrupt the BBB via a cascade of pathological events, such as the release of inflammatory cytokines, accumulation of extracellular adenosine, and the reduction of tight junction integrity. While TBI initially disrupts the BBB via shearing and rupturing forces of the mechanical injury, it also subsequently leads to a similar cascade of events as alcohol. The proposed studies will use adolescent female and male rats subjected to a series of four mTBIs interspersed with episodes of alcohol exposure to test the hypothesis that adolescent alcohol exposure exacerbates repeated mild traumatic brain injury (rmTBI)-induced damage to the BBB and increases expression of dementia-related markers. Proof of principle studies will use pharmacological approaches to examine whether alcohol-mediated enhanced BBB disruption contributes to the increased risk for dementia.