Does oxaloacetate preserve mitochondrial function in the aged brain?

Abstract

AbstractBackgroundAge is the main risk factor for many neurodegenerative disorders including Alzheimer’s disease (AD). One hallmark of brain aging is mitochondrial impairment resulting in bioenergetic dysfunction. Therefore, limiting age‐related decline in mitochondrial function may be an attractive therapeutic strategy to mitigate the risk of AD. Oxaloacetate (OAA) is a metabolic intermediate in the TCA cycle, gluconeogenesis, and amino acid biosynthesis. Treatment with OAA has been shown to enhance neuronal bioenergetics, neurogenesis, and mitochondrial biogenesis in young adult mice, but its effects in aged subjects are unknown. We sought to determine whether OAA treatment in aged rats can alter brain metabolism and mitochondrial function.MethodIn aged male F344 rats (20‐22 months) we used in vivo proton magnetic resonance spectroscopy (1H‐MRS) to obtain baseline neurometabolic readings from two regions of interest: Ctx+ (cortex and subcortical tissue) and Hipp (hippocampus and dorsal striatum). We then treated rats with 1 g/kg/day i.p. OAA (n=14) or vehicle (n=14) for 7 days, followed by post‐treatment 1H‐MRS scans. On day 8 we used an Oxygraph‐2k to compare brain mitochondrial respiration in the OAA vs. vehicle‐treated groups.ResultOAA treatment significantly increased levels of N‐acetylaspartate, glutamate, aspartate, phosphocreatine, lactate, alanine, and ascorbate in a region‐dependent manner. No significant differences were observed in mitochondrial respiratory flux between the OAA and vehicle‐treated groups.ConclusionAfter 1 week of treatment with OAA, aged rats showed changes in brain metabolites linked with bioenergetic function but did not show significant differences in the kinetics or capacity of brain mitochondrial respiration. These findings diverge from previously reported effects of OAA in younger adult mice, highlighting the critical importance of testing novel AD therapies across a range of ages.