Effect of a ketone-based diet and nicotinamide riboside on mitochondrial mechanisms in a DNA repair deficient 3xTg/POLB (/-) Alzheimer’s disease mouse model

Authors

• RJ Pawlosky
• TG Demarest
• MT King
• D Estrada
• VA Bohr
• RL Veech

Abstract

Alzheimer’s disease (AD) modifies brain metabolism including glucose hypometabolism with mitochondrial energy impairments.
We investigated whether a dietary ketone ester (Ket) and a NAD precursor, Nicotinamide Riboside (NR) would impact hippocampal metabolism and restore mitochondrial bioenergetics in wildtype (Wt) and triple transgenic 3xTg AD DNA polymerase-β deficient (AD), male and female mice.
To assess metabolic alterations imparted by Ket and NR alone or in combination, 16 groups - four Wt and four transgenic AD male/female mice were studied. At 65 wks, mice were divided into: A) carbohydrate diet (Carb); B) Carb diet with NR (Carb-NR); C) Ket diet (Ket); and D) Ket diet with NR (Ket-NR) groups and remained on treatment for 12 wks. Mice were euthanized, hippocampi removed and frozen. Glycolytic and TCA cycle intermediates were determined by GC/MS and the ratios of the free mitochondrial [NAD]/[NADH] and ubiquinone (CoQ/CoQH2) couples and the ATP of hydrolysis were calculated from selected metabolites.
Blood ketones were between 1-2 mM in groups C and D. Across several Wt and AD treatment groupings, concentrations of TCA cycle metabolites were greater in males than females. In Wt males NR treatments elevated ketoglutarate and malate. Fumarate concentrations in WT males were associated with ATP energy elevations. In AD males NR treatments increased ATP energy and both NR and Ket treatment restored ATP energy. The Ket diet reduced [NAD]/[NADH] couple to restore the energy of ATP hydrolysis in AD females.
In the 3xTg/POLB(+/-) AD mouse model sex and experimental treatments diverged in restoring mitochondrial energetics.

Scientific Focus Area: Neuroscience

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