Zhao Yuhai, Bhattacharjee Surjyadipta, Jones Brandon M, Hill Jim, Dua Prerna, Lukiw Walter J
LSU Neuroscience Center, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA.
Mol Neurobiol. 2014 Aug;50(1):97-106. doi: 10.1007/s12035-013-8595-3. Epub 2013 Nov 29.
Inducible microRNAs (miRNAs) perform critical regulatory roles in central nervous system (CNS) development, aging, health, and disease. Using miRNA arrays, RNA sequencing, enhanced Northern dot blot hybridization technologies, Western immunoblot, and bioinformatics analysis, we have studied miRNA abundance and complexity in Alzheimer's disease (AD) brain tissues compared to age-matched controls. In both short post-mortem AD and in stressed primary human neuronal-glial (HNG) cells, we observe a consistent up-regulation of several brain-enriched miRNAs that are under transcriptional control by the pro-inflammatory transcription factor NF-kB. These include miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a, and miRNA-155. Of the inducible miRNAs in this subfamily, miRNA-125b is among the most abundant and significantly induced miRNA species in human brain cells and tissues. Bioinformatics analysis indicated that an up-regulated miRNA-125b could potentially target the 3'untranslated region (3'-UTR) of the messenger RNA (mRNA) encoding (a) a 15-lipoxygenase (15-LOX; ALOX15; chr 17p13.3), utilized in the conversion of docosahexaneoic acid into neuroprotectin D1 (NPD1), and (b) the vitamin D3 receptor (VDR; VD3R; chr12q13.11) of the nuclear hormone receptor superfamily. 15-LOX and VDR are key neuromolecular factors essential in lipid-mediated signaling, neurotrophic support, defense against reactive oxygen and nitrogen species (reactive oxygen and nitrogen species), and neuroprotection in the CNS. Pathogenic effects appear to be mediated via specific interaction of miRNA-125b with the 3'-UTR region of the 15-LOX and VDR messenger RNAs (mRNAs). In AD hippocampal CA1 and in stressed HNG cells, 15-LOX and VDR down-regulation and a deficiency in neurotrophic support may therefore be explained by the actions of a single inducible, pro-inflammatory miRNA-125b. We will review the recent data on the pathogenic actions of this up-regulated miRNA-125b in AD and discuss potential therapeutic approaches using either anti-NF-kB or anti-miRNA-125b strategies. These may be of clinical relevance in the restoration of 15-LOX and VDR expression back to control levels and the re-establishment of homeostatic neurotrophic signaling in the CNS.
可诱导的微小RNA（miRNA）在中枢神经系统（CNS）发育、衰老、健康和疾病中发挥着关键的调节作用。我们使用miRNA阵列、RNA测序、增强型Northern斑点杂交技术、蛋白质免疫印迹和生物信息学分析，研究了与年龄匹配的对照相比，阿尔茨海默病（AD）脑组织中miRNA的丰度和复杂性。在死后短时间的AD以及应激的原代人神经胶质（HNG）细胞中，我们观察到几种脑富集的miRNA持续上调，这些miRNA受促炎转录因子NF-κB的转录控制。其中包括miRNA-9、miRNA-34a、miRNA-1,25b、miRNA-146a和miRNA-155。在这个亚家族的可诱导miRNA中，miRNA-125b是人类脑细胞和组织中最丰富且显著诱导的miRNA之一。生物信息学分析表明，上调的miRNA-125b可能靶向编码以下物质的信使核糖核酸（mRNA）的3'非翻译区（3'-UTR）：（a）一种15-脂氧合酶（15-LOX；ALOX15；17号染色体p13.3），用于将二十二碳六烯酸转化为神经保护素D1（NPD1）；（b）核激素受体超家族的维生素D3受体（VDR；VD3R；12号染色体q13.11）。15-LOX和VDR是脂质介导的信号传导、神经营养支持、抵抗活性氧和氮物种（活性氧和氮物种）以及CNS神经保护中必不可少的关键神经分子因子。致病作用似乎是通过miRNA-125b与15-LOX和VDR信使核糖核酸（mRNA）的3'-UTR区域的特异性相互作用介导的。因此，在AD海马CA1区和应激的HNG细胞中，15-LOX和VDR的下调以及神经营养支持的缺乏可能可以用单一的可诱导促炎miRNA-125b的作用来解释。我们将回顾关于这种上调的miRNA-125b在AD中的致病作用的最新数据，并讨论使用抗NF-κB或抗miRNA-125b策略的潜在治疗方法。这些方法可能在将15-LOX和VDR表达恢复到对照水平以及重新建立CNS中稳态神经营养信号传导方面具有临床相关性。
