Amyloid β-Oligomers Inhibit the Nuclear Ca(2+) Signals and the Neuroprotective Gene Expression Induced by Gabazine in Hippocampal Neurons

Hippocampal neuronal activity generates dendritic and somatic Ca(2+) 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(2+) 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(2+) signals and on the Ca(2+)-dependent expression of neuroprotective genes. To induce neuronal activity, neuron-enriched primary hippocampal cultures were treated with the GABA(A) receptor blocker gabazine (GBZ), and nuclear Ca(2+) signals were measured in AβOs-treated or control neurons transfected with a genetically encoded nuclear Ca(2+) sensor. Incubation (6 h) with AβOs significantly reduced the nuclear Ca(2+) 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(2+) signals, disrupt key neuroprotective gene expression pathways required for hippocampal-dependent learning and memory processes.