Samuelsson Malin, Fisher Linda, Iverfeldt Kerstin
Department of Neurochemistry and Neurotoxicology, Stockholm University, Sweden.
Int J Mol Med. 2005 Sep;16(3):449-53.
An increasing body of evidence suggests that beta-amyloid (Abeta) and activated glial cells play a crucial part in the pathogenesis of Alzheimer's disease (AD). Activated glial cells surrounding the senile plaques, formed by Abeta peptides, have been proposed to promote neurodegeneration by producing putatively toxic factors, including the inflammatory cytokine interleukin-1beta (IL-1beta). Elevated levels of both IL-1beta and activated nuclear factor kappaB (NF-kappaB), a key transcription factor regulating a wide variety of inflammatory genes, have been found in the brains of AD patients. In this study, we have investigated the ability of the Abeta(25-35) peptide and IL-1beta, either alone or together, in activating NF-kappaB in glial cells. Mixed primary glial cells from rat were treated with IL-1beta and/or Abeta(25-35), and NF-kappaB binding activity was analyzed by electophoretic mobility shift assay. We observed that the induction of NF-kappaB binding activity induced by either IL-1beta or Abeta(25-35) showed a peak at 30 min, and significantly declined after 2 h. The induced NF-kappaB activation persisted after 24 h and even seemed to increase in cells treated with Abeta(25-35). The activation of NF-kappaB by Abeta(25-35) was shown to be dose-dependent. In addition, Abeta(25-35) potentiated the effect of IL-1beta in a dose-dependent manner when co-stimulating the cells. The potentiating effect of Abeta(25-35) on IL-1beta-induced NF-kappaB binding activity was observed after 30 min, 2 h and 24 h, and did not significantly differ over time. A possible explanation is that when glial cells are stimulated by inflammatory factors in the presence of Abeta peptides or senile plaques, the NF-kappaB negative feedback regulation is no longer functional.
越来越多的证据表明，β-淀粉样蛋白（Aβ）和活化的胶质细胞在阿尔茨海默病（AD）的发病机制中起关键作用。有人提出，由Aβ肽形成的老年斑周围的活化胶质细胞通过产生包括炎性细胞因子白细胞介素-1β（IL-1β）在内的可能有毒的因子来促进神经退行性变。在AD患者的大脑中发现IL-1β和活化的核因子κB（NF-κB，一种调节多种炎症基因的关键转录因子）水平均升高。在本研究中，我们研究了Aβ（25-35）肽和IL-1β单独或共同激活胶质细胞中NF-κB的能力。用IL-1β和/或Aβ（25-35）处理来自大鼠的混合原代胶质细胞，并通过电泳迁移率变动分析来分析NF-κB结合活性。我们观察到，IL-1β或Aβ（25-35）诱导的NF-κB结合活性在30分钟时达到峰值，并在2小时后显著下降。诱导的NF-κB活化在24小时后持续存在，在用Aβ（25-35）处理的细胞中甚至似乎有所增加。Aβ（25-35）对NF-κB的激活呈剂量依赖性。此外，当共同刺激细胞时，Aβ（25-35）以剂量依赖性方式增强IL-1β的作用。在30分钟、2小时和24小时后均观察到Aβ（25-35）对IL-1β诱导的NF-κB结合活性的增强作用，且随时间无显著差异。一种可能的解释是，当胶质细胞在存在Aβ肽或老年斑的情况下受到炎性因子刺激时，NF-κB负反馈调节不再起作用。
