AD and TBI: Converging on Brain Energy Metabolism

Traumatic brain injury (TBI) is a significant public health concern that disproportionately affects military personnel. While some people, like military personnel, place themselves at a higher risk for experiencing a TBI, no one is immune to the chance that a TBI could happen to them at any time. Will the TBI cause lasting changes to a person's mood, ability to learn, or develop degenerative brain disease, is a question that the families and the individual who suffered a TBI want to know. The answer to that question depends a lot on the severity of the TBI; but, even for a TBI of mild severity — which is estimated to occur to at least 1.5 million Americans a year — the data suggests that a mild TBI could accelerate the onset of dementia. Fortunately, there is not a one-to-one relationship, where a TBI will lead to the development of Alzheimer's disease (AD) or any other causes of dementia. The lack of a direct connection suggests that some people have a selective vulnerability to develop a neurodegenerative disease after experiencing a TBI. The cause of the selective vulnerability is not fully understood but is most likely an interaction between genetic vulnerabilities, and things like age and accumulation of misfolded proteins in the brain. Understanding the interrelationship between TBI and AD and related dementias is of critical importance to provide a means of treatment, and to identify people who would benefit most from treatment. Through a series of collaborations that have developed over the last few years with experts in brain energy metabolism, paired with experts in AD and TBI, we have uncovered an unexpected convergence point where both TBI and AD-related genetic influences affect the energy metabolism of the brain. Our data suggest that TBI and AD effect on energy metabolism are likely at least additive by targeting different aspects of brain energy metabolism. For instance, we have found that a TBI can cause chronic deficits in the ability of mitochondria to produce energy; while, the genetic risk factor, APOE4, affects the brain's ability to process glucose. Using our well-established mouse model of mild closed head injury (CHI), we will fill critical gaps in our knowledge about how a TBI interacts with AD-risk at the level of brain energy metabolism (Aim 1). We will use blood plasma metabolomics to determine if we can correlate these biomarkers with changes in brain energy metabolism (Aim 2). These experiments will provide a means to determine if someone would potentially benefit from treatment targeting the deficits in brain energy metabolism. Finally, we will determine if we can improve brain energy metabolism by using alternative fuel to bypass the blocks caused by a TBI (Aim 3)