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

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

Paris

Congreso; 26th Biennial Meeting of the International Society for Neurochemistry (ISN).; 2017

ISN-ESN

Characterization and comprehension of the Alzheimer?s Disease (AD) presymptomatic stage would help to better understand disease progression, develop early detection methods and improve treatment. Our main goal was to perform untargeted NMR metabolomicsin hemizygous McGill-R-Thy1-APP (TG!) rats which compiles several biochemical and neuropathological characteristics detected in presymptomatic human AD brain. Experiments were 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 study changes at central and systemic levels. Hippocampus were homogenized in 80% methanol to extract solublemetabolites. Differences between TG+/- and WT were analyzed by 1D 1H-NMR, whereas metabolite identification was performed by 2D NMR and confirmed by spiking with standard compounds. Experiments were carried out on a Bruker Avance II spectrometeroperating at 600.3 MHz. Only few metabolites 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 already described increase in presymptomatic AD patients. By contrast to what was described using MRI in dorsal hippocampus of homozygous McGill-R-Thy1-APP rat, which mimic late stages of AD, wedid not find significant decrements in the N-acetylaspartate, GABA, and Glutamate levels in TG+/- as compared to WT. However, we did observe increased levels of NAD/H (p < 0.01) and decreased levels of nicotinamide (p < 0.01). These two metabolites are part ofthe NAD+ salvage pathway, which is essential to 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 metabolic processes, are taking place in the brain at early stages of AD.