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

Correlative evidence has shown that an acute injurious event, such as a traumatic brain injury (TBI) can be the trigger for the clinical presentation of neurological symptoms associated with dementia, and subsequent further neurological decline. A TBI is a well-known risk factor for Alzheimer’s disease. A TBI appears to worsen the neurological symptoms of all causes of dementias, leading to an early clinical diagnosis of the dementia. With advance age, the body fails to recover from an injury as well as when younger, and depending on other factors (i.e. genetics, or protein aggregates in the brain) can compound on other age-related pathologies and accelerate the conversion to clinical syndrome. Our preliminary evidence shows that a TBI also causes chronic deficits in energy metabolism and neuroinflammation, which compound on the deficits in energy metabolism and increased neuroinflammation seen with aging and amyloid-beta. Thus, energy deficits and neuroinflammation may be a point of inflection in the neurogenerative cascade that can enhance onset of neurological functional decline, as well as providing a disease-modifying therapeutic target. The long-term goal of this project is to provide translational insight in safe treatments to be used after an acute injurious event in a population at risk for developing Alzheimer’s disease due to presence of amyloid-beta in the brain. We have identified Beta-hydroxybutyrate (BHB; 3-hydroxybutyric acid), as safe multimodal intervention that target both mitochondrial dysfunction and neuroinflammation, and thus is a promising disease-modifying therapeutic that warrants further preclinical testing. 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 the in cases of starvation ketones provide can provide as much 70% of the brain’s energy. BHB is an alternative biofuel, that can bypass common blockages in the electron transport system caused by aging, amyloid-beta, and TBI, which decrease mitochondrial bioenergetics. BHB has also been shown to suppress inflammation via an inflammasome-dependent and HCA2-dependent mechanism. We will test the central hypothesis of that BHB will be effective at reducing functional deficits seen in APP/PS1 KI mice following a mild TBI through both energetic and neuroinflammatory / HCA2 dependent mechanisms, in three specific aims (SA). SA1: Dose-dependent effects of BHB. 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 of the HCA2 receptor through loss of function experiment. Our proposed work will define the potential of BHB as a safe post-TBI neuroprotective agent and will define the mechanism of action of BHB in the TBI + Alzheimer’s disease context. A significant way to reduce the overall burden of Alzheimer’s disease is to identify modifiable risk factors, which could be avoided or treated, that would slow or prevent the onset of Alzheimer’s disease. Traumatic brain injury is a well-established environmental risk factor for the development of Alzheimer’s disease. Completion of these studies will uncover the largely unexplored therapeutic approach of Beta hydroxybutyrate for individuals exposed to a traumatic brain injury to reduce the risk of developing a neurodegenerative disease.