High intracellular concentrations of amyloid-beta block nuclear translocation of phosphorylated CREB
High intracellular concentrations of amyloid-beta block nuclear translocation of phosphorylated CREB
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DOI：
10.1111/j.1471-4159.2007.04704.x
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发表时间：
2007-10-01
影响因子：
4.7
通讯作者：
Cuello, A. C.
中科院分区：
文献类型：
--
作者：
Arvanitis, D. N.;Ducatenzeiler, A.;Cuello, A. C.
β-淀粉样多肽(A-β)被认为是阿尔茨海默病的致病因素。尽管有大量报道描述了细胞外AP的神经毒性作用，但细胞内Aβ(IAβ)的作用尚未阐明。我们先前已经证明，在大鼠嗜铬细胞瘤细胞中，中等水平的AP表达导致磷酸化细胞外信号调节激酶(ERK1/2)/2的上调，以及环磷酸腺苷反应元件(CRE)调节的基因表达的上调；然而，没有研究细胞内高水平AP的影响。为了实现这一目标，我们构建了在人类细胞系中内源性产生不同表达水平的IA beta的结构。我们在神经人类细胞系中显示了对IAβ的双峰反应。适度增加内源性Aβ，可通过CREB活化和突触素1核转位，上调某些环磷酸腺苷反应元件结合蛋白(CREB)反应基因，如早老素1、早老素2、脑源性神经营养因子，以及mRNA和蛋白质水平。另一方面，高负荷的Aβ导致CREB持续的过度磷酸化，不会转移到细胞核，也不会刺激CRE调节的基因表达的激活。我们的研究表明，IAβ水平的变化可能会影响导致CREB磷酸化的信号机制、其核转位以及参与Aβ产生和突触可塑性的CRE调节基因的相反方向。
The beta-amyloid peptide (A beta) is considered responsible for the pathogenesis of Alzheimer's disease. Despite the magnitude of reports describing a neurotoxic role of extracellular AP, the role for intracellular A beta (iA beta) has not been elucidated. We previously demonstrated that in rat pheochromocytoma cells expression of moderate levels of AP results in the up-regulation of phospho-extracellular signal-regulated kinases (ERK1)/2 along with an elevation of cyclic AMP-response element (CRE)-regulated gene expression; however, the effect of high intracellular levels of AP were not examined. Towards this goal we generated constructs that endogenously produce different expression levels of iA beta in a human cell line. We show a bimodal response to iA beta in a neural human cell line. A moderate increase of endogenous A beta up-regulates certain cyclic AMP-response element-binding protein (CREB) responsive genes such as presenilin 1, presenilin 2, brain-derived neurotrophic factor, and mRNA and protein levels by CREB activation and Synapsin 1 nuclear translocation. On the other hand, high-loads of A beta resulted in sustained hyper-phosphorylation of CREB that did not translocate to the nucleus and did not stimulate activation of CRE-regulated gene expression. Our study suggests that variations in levels of iA beta could influence signaling mechanisms that lead to phosphorylation of CREB, its nuclear translocation and CRE-regulated genes involved in production of A beta and synaptic plasticity in opposite directions.