Zhao Yuhai, Bhattacharjee Surjyadipta, Jones Brandon M, Dua Prerna, Alexandrov Peter N, Hill James M, Lukiw Walter J
Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112-2272, USA.
Neuroreport. 2013 Apr 17;24(6):318-23. doi: 10.1097/WNR.0b013e32835fb6b0.
Genetic deficits and loss of function for the triggering receptor expressed in myeloid cells 2 (TREM2; encoded at chr6p21.1), a transmembrane spanning stimulatory receptor of the immunoglobulin/lectin-like gene superfamily, have been associated with deficiencies in phagocytosis and the innate immune system in Alzheimer's disease. In this study, we provide evidence that TREM2 is downregulated in samples of sporadic Alzheimer hippocampal CA1 compared with age-matched controls. A nuclear factor-кB (NF-кB)-sensitive miRNA-34a (encoded at chr1p36.22), upregulated in Alzheimer's disease, was found to target the 299 nucleotide human TREM2 mRNA 3'-untranslated region (3'-UTR) and downregulate the expression of a TREM2-3'-UTR reporter vector. A stabilized anti-miRNA-34a (AM-34a) quenched this pathogenic response. The results suggest that an epigenetic mechanism involving an NF-кB-mediated, miRNA-34a-regulated downregulation of TREM2 expression may shape innate immune and phagocytic responses that contribute to inflammatory neurodegeneration.
髓系细胞触发受体2（TREM2；位于6号染色体p21.1编码）是免疫球蛋白/凝集素样基因超家族的一种跨膜刺激性受体，其基因缺陷和功能丧失与阿尔茨海默病中吞噬作用和先天免疫系统的缺陷有关。在本研究中，我们提供证据表明，与年龄匹配的对照组相比，散发性阿尔茨海默病海马CA1区样本中TREM2表达下调。在阿尔茨海默病中上调的核因子-кB（NF-кB）敏感的微小RNA-34a（位于1号染色体p36.22编码），被发现靶向299个核苷酸的人类TREM2 mRNA 3'-非翻译区（3'-UTR），并下调TREM2-3'-UTR报告载体的表达。一种稳定的抗微小RNA-34a（AM-34a）可消除这种致病反应。结果表明，一种涉及NF-кB介导、微小RNA-34a调节的TREM2表达下调的表观遗传机制，可能会影响导致炎症性神经变性的先天免疫和吞噬反应。
