Translational Approaches to Mitigate Enhanced Alzheimer’s Disease Risk Following a Mild TBI

ABSTRACT A traumatic brain injury (TBI) is a well-known risk factor for Alzheimer's disease. There is not a one-to-one relationship, where a TBI will lead to the development of Alzheimer's disease. The lack of a direct connection suggests a selective vulnerability. Problematically, when a person has a mild TBI, it is not possible to know if they will recover without an impact on their brain health or if they have now increased their vulnerability to developing Alzheimer's disease. What can be done? One approach is a broad administration of therapy shortly after the injury. Since this approach requires treating some people who would recover from the TBI without intervention, the benefit-to-risk ratio must be very high. That is, you do not want to cause harm by giving an unneeded drug. Our long-term goal is to identify safe treatments to be used after a mild TBI in an older adult population to lessen the chance of developing Alzheimer's disease. There are currently no FDA approved drugs to be used after a mild TBI to reduce secondary injury mechanisms. We believe that not treating after a mild TBI is a missed opportunity, but the treatment needs to be safe. Our preliminary evidence shows that a TBI causes deficits in energy metabolism and increased neuroinflammation, both of which are exacerbated by preexisting proteinopathies, such as amyloid-beta. To target these mechanisms, we have identified Beta- hydroxybutyrate (BHB; 3-hydroxybutyric acid) as a safe multimodal intervention. BHB is a ketone body, which is continuously produced by the liver at low levels but can rise above 1mM during periods of fasting, calorie restriction, prolonged exercise, or by the ketogenic diet. Clinically, BHB is safe to be administered orally, BHB rapidly crosses the blood-brain-barrier, and in cases of starvation, ketones can provide as much as 70% of the brain's energy. BHB is an alternative biofuel, that can bypass blockages in the electron transport system caused by amyloid-beta, and TBI, which decrease mitochondrial bioenergetics. BHB has also been shown to suppress inflammation via an inflammasome-dependent mechanism and by binding to a recently deorphanized GPCR called HCA2. We will test the central hypothesis that BHB will be effective at reducing functional deficits seen in APP/PS1 KI mice following a mild TBI through both energetic and neuroinflammatory dependent mechanisms, in three specific aims (SA). SA1: Dose-dependent effects of BHB on mitochondrial function and neuroinflammation after TBI. SA2: Define the immunomodulatory properties of the HCA2 receptor, via dose-dependent effects of niacin, a high-affinity HCA2 agonist. SA3: Define the immunomodulatory properties BHB through the HCA2 receptor through loss of function experiment. Our work seeks to address the mechanisms associated with the increased fragility of the older brain which keeps it from recovering from a mild TBI. We also will define the therapeutic potential of the BHB/HCA2 axis as a post-TBI neuroprotective strategy for use in a population at risk for Alzheimer's disease.