Decreased energy metabolism is an invariant feature of the brains of Alzheimer?s disease (AD) patients, yet the specific use of pharmacologic strategies to manipulate energy metabolism in the brain remains relatively untested. We have developed a new approach to treating AD that utilizes fundamental biochemical principles such as the law of mass action, and additionally exploits redox ratios (in particular NAD+/NADH coupling) that gate some bioenergetic fluxes. Our overarching hypothesis is that enhancing brain respiration flux, glycolysis flux, or both will benefit AD patients. We have created new drugs that induce a near-ketogenic state, which we propose will enhance brain metabolism and reduce amyloid pathology. The purpose of this exploratory R21 proposal is test our hypothesis that our new ?bioenergetic? drug approach will increase brain energy utilization and reduce amyloid plaque formation in both aged wild-type and transgenic mice. We recently completed a Phase 1B clinical trial of the bioenergetic compound oxaloacetate (OAA) in AD patients with mild dementia (NCT02593318), which showed increased default mode network brain glucose utilization by 18FDG-PET and increased parietal and frontoparietal reduced glutathione on magnetic resonance spectroscopy (MRS) scans. However, enhancement was only seen at the highest doses of 2g/day. We have developed new prodrugs that combine OAA with additional bioenergetic molecules that we propose will enhance ketone bodies and pyruvate levels in the brain, synergistically increasing brain metabolism.
Aim 1 will test our hypothesis that prodrugs of OAA and ?-hydroxybutyrate (BHB) or propylene glycol (PG) can increase available ketone bodies and pyruvate levels, respectively, and affect brain metabolism.
Aim 2 will further test this hypothesis in transgenic mice that have rapid accumulation of amyloid plaques (5xFAD). We will further verify activity in aged wild-type mice, which more accurately recapitulate the whole body (and thus brain) declines in mitochondria function and imbalances in ketone bodies and glucose metabolism. In summary, bioenergetic medicine, i.e. the correction of age-induced mitochondria dysfunction, is a fundamentally different approach to AD therapy from current clinical approaches. The biological studies we propose here could show that there is a firm rationale to develop new clinical drugs that take advantage of multiple bioenergetic mechanisms to reduce brain amyloidosis and age-related brain metabolic decline ? spurring development of bioenergetic pharmaceutical approaches.
Mitochondria function decreases with aging, and these losses in function and biological defects play a large role in the cognitive decline observed in Alzheimer?s disease. For these reasons, we are developing new medicines that target mitochondrial dysfunction in Alzheimer?s disease. The animal studies planned in this proposal will elucidate how these medicines improve brain energy utilization, direct us in the development of even better drugs, and answer critical developmental questions before human trials can begin.