将激活突触 NMDA 受体诱导的 CREB 信号与大脑皮层神经元短暂暴露于寡聚淀粉样蛋白-β肽联系起来

IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of Neurochemistry Pub Date : 2024-09-12 DOI:10.1111/jnc.16222
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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引用次数: 0

摘要

淀粉样β肽寡聚体(AβO)被认为是阿尔茨海默病(AD)中最终导致选择性神经元死亡的一系列事件的 "首要动因"。然而,AβO 引发的最初事件尚未得到明确界定。已知突触(Syn)N-甲基-d-天冬氨酸受体(NMDAR)可激活cAMP反应元件结合蛋白(CREB),CREB是一种转录因子,参与细胞存活、记忆形成和突触可塑性相关基因的表达,而突触外(ESyn)NMDAR的激活则与兴奋毒性事件有关。在 AD 脑中,CREB 磷酸化/激活被证明发生了改变,同时细胞内 Ca2+ (Ca2+i) 的平衡失调。因此,在这项研究中,我们分析了急性/早期和长期 AβO 介导的 CREB 激活变化,这些变化涉及成熟大鼠皮质神经元中的 Syn 或 ESyn NMDARs。我们的研究结果表明,急性 AβO 暴露会产生磷酸化 CREB 的早期增加,反映了 CREB 的活性,这一过程是通过 Syn NMDAR 介导的 Ca2+ 流入发生的。数据还表明,长期(24 小时)暴露于 AβO 会损害与 Ca2+ 依赖性 CREB 磷酸化/激活、核 CREB 水平及相关靶基因(即 Bdnf、Gadd45γ 和 Btg2)有关的突触功能。数据表明,早期或长期暴露于 AβO 后,成熟的大脑皮层神经元会通过激活 CREB 信号通路产生双重效应,这与 Syn NMDARs 的激活有关。
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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
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来源期刊
Journal of Neurochemistry
Journal of Neurochemistry 医学-神经科学
CiteScore
9.30
自引率
2.10%
发文量
181
审稿时长
2.2 months
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.
期刊最新文献
Issue Information Neurofilament heavy phosphorylated epitopes as biomarkers in ageing and neurodegenerative disease. A special focus on polyadenylation and alternative polyadenylation in neurodegenerative diseases: A systematic review. Alterations of endocannabinoid signaling and microglia reactivity in the retinas of AD-like mice precede the onset of hippocampal β-amyloid plaques. Convergent effects of synthetic glucocorticoid dexamethasone and amyloid beta in human olfactory neurosphere-derived cells.
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