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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 ma...

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Detalles Bibliográficos
Autores principales: Lobos, Pedro, Vega-Vásquez, Ignacio, Bruna, Barbara, Gleitze, Silvia, Toledo, Jorge, Härtel, Steffen, Hidalgo, Cecilia, Paula-Lima, Andrea
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10669355/
https://www.ncbi.nlm.nih.gov/pubmed/38001825
http://dx.doi.org/10.3390/antiox12111972
Descripción
Sumario: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.