Untargeted 1 H-NMR spectrometry to detect central and systemic metabolic changes in a rat model of early Alzheimer's disease

DALMASSO, MC; SMAL, C; MORELLI, L; FERRARI, CC; CUELLO, AC; ARAN, M; CASTAÑO, EM

Paris

Congreso; ISN-ESN 2017 Meeting; 2017

International Society for Neurochemistry

Characterization and comprehensionof the Alzheimer?s Disease (AD) presymptomatic stage would help to betterunderstand disease progression, develop early detection methods and improvetreatment. Our main goal was to perform untargeted NMR metabolomics in hemizygousMcGill-R-Thy1-APP (TG+/-) rats which compiles several biochemical andneuropathological characteristics detected in presymptomatic human AD brain. Experimentswere performed in male TG+/- (n= 8) and non-transgenic littermate (WT) (n= 8)rats of 9 months of age. CSF, hippocampus, and plasma were collected to studychanges at central and systemic levels. Hippocampus were homogenized in 80%methanol to extract soluble metabolites. Differences between TG+/- and WT wereanalyzed by 1D 1H-NMR, whereas metabolite identification wasperformed by 2D NMR experiments and confirmed by spiking withstandard compounds. Experiments were carried out on a Bruker Avance IIspectrometer operating at 600,3 MHz. Only fewmetabolites changed between TG+/- and WT rats in each sample type (n=2 in CSF,  n=1 in plasma, and n=3 in hippocampus). In plasma,lactate levels were higher in TG+/- than WT (p<0.07), resembling the alreadydescribed increase in presymptomatic AD patients. By contrast to what wasdescribed using MRI in dorsal hippocampus of  homozygous McGill-R-Thy1-APPrat, which mimic late stages of AD, we did not find significantdecrements in the N-acetylaspartate, GABA, and Glutamate levels in TG+/- ascompared to  WT. However, we did observeincreased levels of NAD/H (p<0.01) and decreased levels of nicotinamide (p<0.03).These two metabolites are part of the NAD+ salvage pathway, which is essentialto maintain the NAD+ pool. Our results suggest that a rise in NAD+ synthesis,probably to ameliorates mitochondiral disfunction, and/or an impairment in NAD+conssumig enzimes activity like sirtuins, affecting epigenetic and metabolicprocesses, are taking place in the brain at early stages of AD.