Pyruvate Carboxylase and Pentose Phosphate Fluxes are Reduced in AβPP-PS1 Mouse Model of Alzheimer's Disease: A 13 C NMR Study

Abstract

Although pyruvate dehydrogenase (PDH) is the major pathway of glucose metabolism and source for energy production, pyruvate carboxylase (PC) and pentose phosphate pathway (PPP) account for a significant fraction of glucose oxidation in the mature central nervous system. Flux through the PDH pathway has been reported to be reduced in Alzheimer's disease (AD) patients as well as in animal models of AD. However, fluxes through the PPP and PC pathways have not been explored under conditions of AD. The present study investigates the fluxes of PC and PPP in a 20-month-old AβPP-PS1 mouse model of AD using ¹³C NMR spectroscopy together with an infusion of [2-¹³C]glucose. Mice were also administered [1,6-¹³C₂]glucose or [1-¹³C]glucose for 10 or 90 min, respectively, to investigate PDH flux. AβPP-PS1 mice exhibit a significant reduction in the level of NAA and increase in level of myo-inositol. The flux through PDH was found to be significantly lower in the cerebral cortex (AβPP-PS1 0.39 ± 0.08; control 0.77 ± 0.08 μmol/g/min), hippocampus (AβPP-PS1 0.31 ± 0.04; control 0.64 ± 0.12 μmol/g/min), and striatum (AβPP-PS1 0.34 ± 0.06; control 0.56 ± 0.03 μmol/g/min) of AβPP-PS1 as compared with control mice. The fluxes through PC (AβPP-PS1 0.037 ± 0.006, control 0.079 ± 0.013 μmol/g/min) and PPP (AβPP-PS1 0.024 ± 0.005; control 0.062 ± 0.022 μmol/g/min) were found to be significantly reduced in AβPP-PS1 mice when compared with age-matched controls. The reduction in the fluxes of PC and PPP may lead to a weakened neural defense system of ammonia detoxification and antioxidant reserve in AβPP-PS1 mice, which may be responsible for the compromised neuronal viability and functions in AD.