Antioxidants<\/p>\n\n\n\n
Lobos, P., Vega-V\u00e1squez, I., Bruna, B., Gleitze, S., Toledo, J., H\u00e4rtel, S., … & Paula-Lima, A.<\/p>\n\n\n\n
Hippocampal neuronal activity generates dendritic and somatic Ca2+<\/sup>\u00a0signals, 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 (A\u03b2Os), the main synaptotoxins engaged in the pathogenesis of Alzheimer\u2019s disease, generate aberrant Ca2+<\/sup>\u00a0signals in primary hippocampal neurons, increase their oxidative tone and disrupt structural plasticity. Here, we explored the effects of sub-lethal A\u03b2Os concentrations on activity-generated nuclear Ca2+<\/sup>\u00a0signals and on the Ca2+<\/sup>-dependent expression of neuroprotective genes. To induce neuronal activity, neuron-enriched primary hippocampal cultures were treated with the GABAA<\/sub>\u00a0receptor blocker gabazine (GBZ), and nuclear Ca2+<\/sup>\u00a0signals were measured in A\u03b2Os-treated or control neurons transfected with a genetically encoded nuclear Ca2+<\/sup>\u00a0sensor. Incubation (6 h) with A\u03b2Os significantly reduced the nuclear Ca2+<\/sup>\u00a0signals and the enhanced phosphorylation of cyclic AMP response element-binding protein (CREB) induced by GBZ. Likewise, incubation (6 h) with A\u03b2Os 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 A\u03b2Os, by inhibiting the generation of activity-induced nuclear Ca2+<\/sup>\u00a0signals, disrupt key neuroprotective gene expression pathways required for hippocampal-dependent learning and memory processes.<\/p>\n\n\n\n