Ketosis restores hippocampal Krebs’ cycle intermediates and potentiates anxiolytic effects in a murine model of Alzheimer's disease

Authors

• RJ Pawlosky
• Y Kashiwaya
• MT King
• RL Veech

Abstract

INTRODUCTION: Insulin is a key regulator of pyruvate dehydrogenase (PDH) and decreased brain sensitivity toward insulin reduces glucose utilization as observed in Alzheimer’s patients. PDH inhibition decreases the flow of pyruvate to mitochondria with concomitant reduction in Krebs’ cycle metabolites, citrate and alpha-ketoglutarate. Ketone metabolism has the potential to restore these metabolites and enhance amino acid biosynthesis. METHODS: D-beta-hydroxybutyrate was incorporated into a diet and fed to one group of 3xTgAd mice for 8 months. At 16 mo, anxiolytic effects were assessed using an open field trial. Mice were euthanized, and hippocampal metabolites analyzed. Strength of associations between metabolites, amino acids and anxiety were examined. RESULTS: Ketotic mice had greater concentrations of citrate, alpha-ketoglutarate and associated amino acids compared to controls. Hippocampal n-acetyl-aspartate strongly correlated with several anxiolytic determinants. DISCUSSION: Ketosis restored Krebs’ cycle citrate in the hippocampus and this was associated with greater concentrations of aspartate and n-acetyl-aspartate commensurate with potent anxiolytic behavioral outcomes.

Scientific Focus Area: Neuroscience

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