Lukiw Walter J, Zhao Yuhai, Cui Jian Guo
Louisiana State University Neuroscience Center, Louisiana State University Health Science Center, New Orleans, Louisiana 70112-2272, USA.
J Biol Chem. 2008 Nov 14;283(46):31315-22. doi: 10.1074/jbc.M805371200. Epub 2008 Sep 18.
Human brains retain discrete populations of micro RNA (miRNA) species that support homeostatic brain gene expression functions; however, specific miRNA abundance is significantly altered in neurological disorders such as Alzheimer disease (AD) when compared with age-matched controls. Here we provide evidence in AD brains of a specific up-regulation of an NF-kappaB-sensitive miRNA-146a highly complementary to the 3'-untranslated region of complement factor H (CFH), an important repressor of the inflammatory response of the brain. Up-regulation of miRNA-146a coupled to down-regulation of CFH was observed in AD brain and in interleukin-1beta, Abeta42, and/or oxidatively stressed human neural (HN) cells in primary culture. Transfection of HN cells using an NF-kappaB-containing pre-miRNA-146a promoter-luciferase reporter construct in stressed HN cells showed significant up-regulation of luciferase activity that paralleled decreases in CFH gene expression. Treatment of stressed HN cells with the NF-kappaB inhibitor pyrollidine dithiocarbamate or the resveratrol analog CAY10512 abrogated this response. Incubation of an antisense oligonucleotide to miRNA-146a (anti-miRNA-146a; AM-146a) was found to restore CFH expression levels. These data indicate that NF-kappaB-sensitive miRNA-146a-mediated modulation of CFH gene expression may in part regulate an inflammatory response in AD brain and in stressed HN cell models of AD and illustrate the potential for anti-miRNAs as an effective therapeutic strategy against pathogenic inflammatory signaling.
人类大脑中保留着离散的微小RNA（miRNA）种群，这些种群支持大脑基因表达的稳态功能；然而，与年龄匹配的对照组相比，在诸如阿尔茨海默病（AD）等神经疾病中，特定miRNA的丰度会发生显著改变。在这里，我们提供证据表明，在AD大脑中，一种对核因子κB（NF-κB）敏感的miRNA-146a特异性上调，该miRNA与补体因子H（CFH）的3'-非翻译区高度互补，CFH是大脑炎症反应的重要抑制因子。在AD大脑以及原代培养的白细胞介素-1β、β淀粉样蛋白42（Aβ42）和/或氧化应激的人类神经（HN）细胞中，观察到miRNA-146a上调并伴随CFH下调。在应激的HN细胞中，使用含NF-κB的前体miRNA-146a启动子-荧光素酶报告构建体转染HN细胞，结果显示荧光素酶活性显著上调，这与CFH基因表达的降低平行。用NF-κB抑制剂吡咯烷二硫代氨基甲酸盐或白藜芦醇类似物CAY10512处理应激的HN细胞可消除这种反应。发现用miRNA-146a的反义寡核苷酸（抗miRNA-146a；AM-146a）孵育可恢复CFH表达水平。这些数据表明，NF-κB敏感的miRNA-146a介导的CFH基因表达调节可能部分调控AD大脑以及AD应激HN细胞模型中的炎症反应，并说明了抗miRNA作为针对致病性炎症信号的有效治疗策略的潜力。
