Hippocampal neuronal activity generates dendritic and somatic Ca signals, which, depending on stimulus intensity, rapidly propagate to the nucleus and induce the expression of transcription factors and genes with crucial roles in cognitive functions. Soluble amyloid-beta oligomers (AβOs), the main synaptotoxins engaged in the pathogenesis of Alzheimer's disease, generate aberrant Ca signals in primary hippocampal neurons, increase their oxidative tone and disrupt structural plasticity. Here, we explored the effects of sub-lethal AβOs concentrations on activity-generated nuclear Ca signals and on the Ca-dependent expression of neuroprotective genes. To induce neuronal activity, neuron-enriched primary hippocampal cultures were treated with the GABA receptor blocker gabazine (GBZ), and nuclear Ca signals were measured in AβOs-treated or control neurons transfected with a genetically encoded nuclear Ca sensor. Incubation (6 h) with AβOs significantly reduced the nuclear Ca signals and the enhanced phosphorylation of cyclic AMP response element-binding protein (CREB) induced by GBZ. Likewise, incubation (6 h) with AβOs significantly reduced the GBZ-induced increases in the mRNA levels of neuronal Per-Arnt-Sim domain protein 4 (Npas4), brain-derived neurotrophic factor (BDNF), ryanodine receptor type-2 (RyR2), and the antioxidant enzyme NADPH-quinone oxidoreductase (Nqo1). Based on these findings we propose that AβOs, by inhibiting the generation of activity-induced nuclear Ca signals, disrupt key neuroprotective gene expression pathways required for hippocampal-dependent learning and memory processes.