Increased expression of the homologue of enhancer-of-split 1 protects neurons from beta amyloid neurotoxicity and hints at an alternative role for transforming growth factor beta1 as a neuroprotector
Increased expression of the homologue of enhancer-of-split 1 protects neurons from beta amyloid neurotoxicity and hints at an alternative role for transforming growth factor beta1 as a neuroprotector
复制标题
DOI：
10.1186/alzrt134
复制
发表时间：
2012-01-01
影响因子：
9
通讯作者：
Rodriguez-Tebar, Alfredo
中科院分区：
文献类型：
--
作者：
Chacon, Pedro J.;Rodriguez-Tebar, Alfredo
简介：阿尔茨海默病（AD）是一种神经退行性疾病，其特征在于β-淀粉样蛋白（A β）在脑中的沉积，其产生进行性神经元损失和痴呆。我们最近证明，A β对培养的海马神经元的有害作用部分是由神经生长因子（NGF）信号传导的拮抗作用引起的，神经生长因子（NGF）信号传导通过阻碍I-κ B α的酪氨酸磷酸化而损害核因子κ B（NF-κ B）的活化。结果，分裂增强子1（Hes 1）基因的同源物的表达下调，并最终失去γ-氨基丁酸（GABA）能连接。研究方法：Hes 1活性在培养的海马神经元中通过过表达Hes 1编码质粒或通过不同方法（过表达I-kappa B激酶b或p65/RelA/NF-κ B）激活NF-κ B上调该基因来促进。或者，将神经元暴露于TGF β 1。通过免疫荧光显微镜分析树突图案化、GABA能连接和细胞存活。实时荧光定量PCR检测Hes 1的表达。NF-κ B活化用双荧光素酶报告基因测定法测定。结果如下：Hes 1的表达可阻断Ab对树突形成和GABA能输入的影响，并阻止培养神经元的死亡。TGF β 1是一种已知的神经保护剂，可通过诱导I-κ B α丝氨酸磷酸化后的NF-κ B活化来抵消Ab的有害作用。事实上，通过诱导Hes 1表达产生的GABA能末端的数量增加了一倍。结论：我们的数据定义了A β介导的细胞死亡所涉及的一些机制，并指出了对抗这种有害活动的潜在方法。
Introduction: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of beta-amyloid (A beta) in the brain, which produces progressive neuronal loss and dementia. We recently demonstrated that the noxious effects of A beta on cultured hippocampal neurons are in part provoked by the antagonism of nerve growth factor (NGF) signalling, which impairs the activation of nuclear factor kappa B (NF-kappa B) by impeding the tyrosine phosphorylation of I-kappa B alpha. As a result, the expression of the homologue of Enhancer-of split 1 (Hes1) gene is downregulated and ultimately, gamma-aminobutyric acid (GABA)-ergic connectivity is lost. Methods: Hes1 activity was promoted in cultured hippocampal neurons by overexpressing a Hes1-encoding plasmid or by upregulating this gene by activating NF-kappa B through different approaches (overexpressing either the I-kappa B kinaseb, or p65/RelA/NF-kappa B). Alternatively neurons were exposed to TGF beta 1. Dendrite patterning, GABAergic connectivity and cell survival were analyzed by immunofluorescence microscopy. Hes1 expression was determined by real-time PCR. NF-kappa B activation was measured using the dual-luciferase reporter assay. Results: The expression of Hes1 abolished the effects of Ab on dendritic patterning and GABAergic input, and it prevented the death of the cultured neurons. TGF beta 1, a known neuroprotector, could counteract the deleterious effects of Ab by inducing NF-kappa B activation following the serine phosphorylation of I-kappa B alpha. Indeed, the number of GABAergic terminals generated by inducing Hes1 expression was doubled. Conclusion: Our data define some of the mechanisms involved in A beta-mediated cell death and they point to potential means to counteract this noxious activity.