I. Luísa Ferreira, Daniela Marinho, Valéria de Rosa, Bárbara Castanheira, Zongwei Fang, Gladys L. Caldeira, Sandra I. Mota, A. Cristina Rego
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In AD brain, CREB phosphorylation/activation was shown to be altered, along with dyshomeostasis of intracellular Ca<jats:sup>2+</jats:sup> (Ca<jats:sup>2+</jats:sup><jats:sub>i</jats:sub>). Thus, in this work, we analyze acute/early and long‐term AβO‐mediated changes in CREB activation involving Syn or ESyn NMDARs in mature rat cortical neurons. Our findings show that acute AβO exposure produce early increase in phosphorylated CREB, reflecting CREB activity, in a process occurring through Syn NMDAR‐mediated Ca<jats:sup>2+</jats:sup> influx. Data also demonstrate that AβO long‐term (24 h) exposure compromises synaptic function related to Ca<jats:sup>2+</jats:sup>‐dependent CREB phosphorylation/activation and nuclear CREB levels and related target genes, namely <jats:italic>Bdnf</jats:italic>, <jats:italic>Gadd45γ</jats:italic>, <jats:italic>and Btg2</jats:italic>. Data suggest a dual effect of AβO following early or prolonged exposure in mature cortical neurons through the activation of the CREB signaling pathway, linked to the activation of Syn NMDARs.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http://www.w3.org/1999/xlink\" mimetype=\"image/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic/jnc16222-fig-0006-m.png\"><jats:alt-text>image</jats:alt-text></jats:graphic></jats:boxed-text>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"20 1","pages":""},"PeriodicalIF":4.2000,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Linking activation of synaptic NMDA receptors‐induced CREB signaling to brief exposure of cortical neurons to oligomeric amyloid‐beta peptide\",\"authors\":\"I. Luísa Ferreira, Daniela Marinho, Valéria de Rosa, Bárbara Castanheira, Zongwei Fang, Gladys L. Caldeira, Sandra I. Mota, A. Cristina Rego\",\"doi\":\"10.1111/jnc.16222\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Amyloid‐beta peptide oligomers (AβO) have been considered “<jats:italic>primum movens</jats:italic>” for a cascade of events that ultimately cause selective neuronal death in Alzheimer's disease (AD). However, initial events triggered by AβO have not been clearly defined. Synaptic (Syn) <jats:italic>N</jats:italic>‐methyl‐<jats:sc>d</jats:sc>‐aspartate receptors (NMDAR) are known to activate cAMP response element‐binding protein (CREB), a transcriptional factor involved in gene expression related to cell survival, memory formation and synaptic plasticity, whereas activation of extrasynaptic (ESyn) NMDARs was linked to excitotoxic events. In AD brain, CREB phosphorylation/activation was shown to be altered, along with dyshomeostasis of intracellular Ca<jats:sup>2+</jats:sup> (Ca<jats:sup>2+</jats:sup><jats:sub>i</jats:sub>). Thus, in this work, we analyze acute/early and long‐term AβO‐mediated changes in CREB activation involving Syn or ESyn NMDARs in mature rat cortical neurons. Our findings show that acute AβO exposure produce early increase in phosphorylated CREB, reflecting CREB activity, in a process occurring through Syn NMDAR‐mediated Ca<jats:sup>2+</jats:sup> influx. Data also demonstrate that AβO long‐term (24 h) exposure compromises synaptic function related to Ca<jats:sup>2+</jats:sup>‐dependent CREB phosphorylation/activation and nuclear CREB levels and related target genes, namely <jats:italic>Bdnf</jats:italic>, <jats:italic>Gadd45γ</jats:italic>, <jats:italic>and Btg2</jats:italic>. 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Linking activation of synaptic NMDA receptors‐induced CREB signaling to brief exposure of cortical neurons to oligomeric amyloid‐beta peptide
Amyloid‐beta peptide oligomers (AβO) have been considered “primum movens” for a cascade of events that ultimately cause selective neuronal death in Alzheimer's disease (AD). However, initial events triggered by AβO have not been clearly defined. Synaptic (Syn) N‐methyl‐d‐aspartate receptors (NMDAR) are known to activate cAMP response element‐binding protein (CREB), a transcriptional factor involved in gene expression related to cell survival, memory formation and synaptic plasticity, whereas activation of extrasynaptic (ESyn) NMDARs was linked to excitotoxic events. In AD brain, CREB phosphorylation/activation was shown to be altered, along with dyshomeostasis of intracellular Ca2+ (Ca2+i). Thus, in this work, we analyze acute/early and long‐term AβO‐mediated changes in CREB activation involving Syn or ESyn NMDARs in mature rat cortical neurons. Our findings show that acute AβO exposure produce early increase in phosphorylated CREB, reflecting CREB activity, in a process occurring through Syn NMDAR‐mediated Ca2+ influx. Data also demonstrate that AβO long‐term (24 h) exposure compromises synaptic function related to Ca2+‐dependent CREB phosphorylation/activation and nuclear CREB levels and related target genes, namely Bdnf, Gadd45γ, and Btg2. Data suggest a dual effect of AβO following early or prolonged exposure in mature cortical neurons through the activation of the CREB signaling pathway, linked to the activation of Syn NMDARs.image
期刊介绍:
Journal of Neurochemistry focuses on molecular, cellular and biochemical aspects of the nervous system, the pathogenesis of neurological disorders and the development of disease specific biomarkers. It is devoted to the prompt publication of original findings of the highest scientific priority and value that provide novel mechanistic insights, represent a clear advance over previous studies and have the potential to generate exciting future research.