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.