Abstract
Because of a decreased sensitivity toward insulin, a key regulator of pyruvate dehydrogenase (PDH), Alzheimer’s patients have lower brain glucose utilization with reductions in Tricarboxylic Acid (TCA) cycle metabolites such as citrate, a precursor to n-acetyl-aspartate. In the 3xTgAd mouse model of Alzheimer’s disease (AD), aging mice also demonstrate low brain glucose metabolism. Ketone metabolism can overcome PDH inhibition and restore TCA cycle metabolites, thereby enhancing amino acid biosynthesis. A ketone ester of d-β-hydroxybutyrate was incorporated into a diet (Ket) and fed to 3xTgAd mice. A control group was fed a calorically matched diet (Cho). At 15 months of age, the exploratory and avoidance-related behavior patterns of the mice were evaluated. At 16.5 months of age, the animals were euthanized, and their hippocampi were analyzed for citrate, α-ketoglutarate, and amino acids. In the hippocampi of the Ket-fed mice, there were higher concentrations of citrate and α-ketoglutarate as well as higher concentrations of glutamate, aspartate and n-acetyl-aspartate compared with controls. There were positive associations between (1) concentrations of aspartate and n-acetyl-aspartate (n = 14, R = 0.9327), and (2) α-ketoglutarate and glutamate (n = 14, R = 0.8521) in animals maintained on either diet. Hippocampal n-acetyl-aspartate predicted the outcome of several exploratory and avoidance-related behaviors. Ketosis restored citrate and α-ketoglutarate in the hippocampi of aging mice. Higher concentrations of n-acetyl-aspartate corresponded with greater exploratory activity and reduced avoidance-related behavior.
Highlights
Many Alzheimer’s patients develop a decrease in brain glucose utilization prior to demonstrating clinical symptoms
The long-term effects of feeding the ketone ester (Ket) diet on several glycolytic intermediates, Tricarboxylic Acid (TCA) cycle metabolites and the cytosolic and mitochondrial redox potentials were described in these 3xTgAd mice [12]
We extend this analysis to an examination of potential associations between (1) the TCA cycle metabolites citrate and α-ketoglutarate, and (2) the amino acids aspartate, n-acetyl aspartate and glutamate
Summary
Many Alzheimer’s patients develop a decrease in brain glucose utilization prior to demonstrating clinical symptoms. One factor that contributes to low brain glucose use is a decrease in brain sensitivity to insulin [1], a key regulator of pyruvate dehydrogenase (PDH) activity [2,3]. Low insulin sensitivity inhibits PDH function, which in turn decreases substrate flow through the Tricarboxylic Acid (TCA) cycle and diminishes metabolite production. The TCA cycle metabolite citrate may be utilized for synthesis of cytosolic acetyl-CoA and oxaloacetate, which is a precursor of aspartic acid. The relative abundance of n-acetyl aspartate, as determined by magnetic resonance spectroscopy, correlates with diminished anxiety-related outcomes in patients with neurological disease [5,6], while its presence in reduced concentrations correlates with advancing age [7] and memory deficits in mouse models [8]
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