Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Amyloid β-Oligomers Inhibit the Nuclear Ca2+ Signals and the Neuroprotective Gene Expression Induced by Hippocampal Neuronal Activity

Pedro Lobos
ORCID logo ,
Ignacio Vega-Vásquez
ORCID logo ,
Barbara Bruna
,
Silvia Gleitze
,
Jorge Toledo
,
Steffen Härtel
,
Cecilia Hidalgo
* ,
Andrea Paula-Lima
* ORCID logo
Version 1 : Received: 13 October 2023 / Approved: 16 October 2023 / Online: 16 October 2023 (16:48:34 CEST)

A peer-reviewed article of this Preprint also exists.

Lobos, P.; Vega-Vásquez, I.; Bruna, B.; Gleitze, S.; Toledo, J.; Härtel, S.; Hidalgo, C.; Paula-Lima, A. Amyloid β-Oligomers Inhibit the Nuclear Ca2+ Signals and the Neuroprotective Gene Expression Induced by Gabazine in Hippocampal Neurons. Antioxidants 2023, 12, 1972. Lobos, P.; Vega-Vásquez, I.; Bruna, B.; Gleitze, S.; Toledo, J.; Härtel, S.; Hidalgo, C.; Paula-Lima, A. Amyloid β-Oligomers Inhibit the Nuclear Ca2+ Signals and the Neuroprotective Gene Expression Induced by Gabazine in Hippocampal Neurons. Antioxidants 2023, 12, 1972.

Abstract

Hippocampal neuronal activity generates dendritic and somatic Ca2+ 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 Ca2+ 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 Ca2+ signals and on the Ca2+-dependent expression of neuroprotective genes. To induce neuronal activity, neuron-enriched primary hippocampal cultures were treated with the GABAA receptor blocker gabazine (GBZ), and nuclear Ca2+ signals were measured in AβOs-treated or control neurons transfected with a genetically encoded nuclear Ca2+ sensor. Incubation (6 h) with AβOs significantly reduced the nuclear Ca2+ 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 Ca2+ signals, disrupt key neuroprotective gene expression pathways required for hippocampal-dependent learning and memory processes.

Keywords

Alzheimer´s disease, Neuronal activity; Synaptotoxicity, Calcium-dependent signaling pathways; Calcium-mediated Gene Expression; Antioxidant Enzyme Expression.

Subject

Biology and Life Sciences, Neuroscience and Neurology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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