Alterations in nitric oxide (•NO) concentration dynamics and bioactivity with age may play an important role in the decay of synaptic and metabolic functions in Alzheimer's disease (AD) by affecting plasticity and mitochondrial function. Here we performed a longitudinal study of the glutamate-NO signaling axis in the hippocampus of the triple transgenic mouse model of AD (3xTgAD). We found that, in the CA1 region, NMDAr-evoked •NO transients exhibited a progressive decrease in intensity with age, more pronounced in 3xTgAD as compared to non-transgenic groups. Age-dependent decrease in basal oxygen consumption was accompanied by a significant decrease in maximal respiratory rate. This prompted us to investigate whether •NO bioactivity may be shifted toward oxidative chemistry associated with neurotoxicity and indeed we observed age-dependent increase in 3-nitrotyrosine staining in the hippocampus, more pronounced in the 3xTgAD groups. We conclude that the biphasic change in •NO dynamics in the hippocampus may, at an early age, mitigate loss of synaptic strength but ultimately is diverted towards increased oxidative damage, which may contribute to energetic crisis.