Expression of the phagocytosis-essential protein TREM2 is down-regulated by an aluminum-induced miRNA-34a in a murine microglial cell line.
Expression of the phagocytosis-essential protein TREM2 is down-regulated by an aluminum-induced miRNA-34a in a murine microglial cell line.
复制标题
DOI：
10.1016/j.jinorgbio.2013.05.010
复制
发表时间：
2013-11
影响因子：
3.9
通讯作者：
Lukiw, Walter J.
中科院分区：
文献类型：
--
作者：
Alexandrov, Peter N.;Zhao, Yuhai;Jones, Brandon M.;Bhattacharjee, Surjyadipta;Lukiw, Walter J.
阿尔茨海默病(AD)的一个关键的经典病理特征是淀粉样β蛋白(Aβ42)多肽的进行性积聚，并聚集成高度难溶的老年斑块核心。导致Aβ42多肽积聚的一个主要因素是脑细胞无法通过吞噬有效地清除过量的Aβ42。跨膜的传感器受体被称为“在髓系细胞中表达的触发受体2”(TREM2；chr6p21)，在感知、识别、吞噬和清除脑细胞中的有害细胞碎片方面是必不可少的，包括神经毒素Aβ42肽。最近，TREM2基因突变与包括阿尔茨海默病在内的神经退行性疾病中淀粉样蛋白的发生有关。在这份报告中，我们提供了证据，当硫酸铝与小胶质细胞孵育时，诱导一个核因子-kB敏感的微型RNA-34a(miRNA-34a；chr1p36)上调，该RNA已知针对TREM2的3‘-非翻译区(3’-UTR)，显著下调TREM2的表达。天然酚类化合物和核因子-kB抑制剂CAPE[2-苯乙基-(2E)-3-(3，4-二羟基苯基)丙烯酸酯；咖啡酸苯乙酯]可有效抑制铝诱导的miRNA-34a上调和TREM2表达下调。这些结果首次表明，表观遗传学机制涉及铝触发的、NF-kB敏感的、miRNA-34a介导的TREM2表达下调，可能会损害吞噬反应，最终导致Aβ42肽在大脑中的聚集、聚集、淀粉样变和炎性变性。
One of the key classical pathological features of Alzheimer’s disease (AD) is the progressive accumulation of amyloid beta (Aβ42) peptides and their coalescence into highly insoluble senile plaque cores. A major factor driving Aβ42 peptide accumulation is the inability of brain cells to effectively clear excessive amounts of Aβ42 via phagocytosis. The trans-membrane spanning, sensor-receptor known as the ‘triggering receptor expressed in myeloid cells 2′ (TREM2; chr6p21) is essential in the sensing, recognition, phagocytosis and clearance of noxious cellular debris from brain cells, including neurotoxic Aβ42 peptides. Recently, mutations in the TREM2 gene have been associated with amyloidogenesis in neurodegenerative diseases including AD. In this report, we provide evidence that aluminum-sulfate, when incubated with microglial cells, induces the up-regulation of an NF-kB-sensitive micro RNA-34a (miRNA-34a; chr1p36) that is known to target the TREM2 mRNA 3′-untranslated region (3′-UTR), significantly down-regulating TREM2 expression. The aluminum-induced up-regulation of miRNA-34a and down-regulation of TREM2 expression was effectively quenched using the natural phenolic compound and NF-kB inhibitor CAPE [2-phenylethyl-(2E)-3-(3,4-dihydroxyphenyl) acrylate; caffeic-acid phenethyl ester]. These results suggest, for the first time, that an epigenetic mechanism involving an aluminum-triggered, NF-kB-sensitive, miRNA-34a-mediated down-regulation of TREM2 expression may impair phagocytic responses that ultimately contribute to Aβ42 peptide accumulation, aggregation, amyloidogenesis and inflammatory degeneration in the brain.
登录
查看更多内容
DOI：
10.1056/nejmoa1211851
发表时间：
2013-01-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guerreiro R;Wojtas A;Bras J;Carrasquillo M;Rogaeva E;Majounie E;Cruchaga C;Sassi C;Kauwe JS;Younkin S;Hazrati L;Collinge J;Pocock J;Lashley T;Williams J;Lambert JC;Amouyel P;Goate A;Rademakers R;Morgan K;Powell J;St George-Hyslop P;Singleton A;Hardy J;Alzheimer Genetic Analysis Group
通讯作者：
Alzheimer Genetic Analysis Group
影响因子：
56.9
作者：
Nimmerjahn, A;Kirchhoff, F;Helmchen, F
通讯作者：
Helmchen, F
影响因子：
4.7
作者：
Melchior B;Garcia AE;Hsiung BK;Lo KM;Doose JM;Thrash JC;Stalder AK;Staufenbiel M;Neumann H;Carson MJ
通讯作者：
Carson MJ
影响因子：
5.6
作者：
Pogue AI;Jones BM;Bhattacharjee S;Percy ME;Zhao Y;Lukiw WJ
通讯作者：
Lukiw WJ
影响因子：
3.1
作者：
Lukiw, WJ;Leblanc, HJ;Bazan, NG
通讯作者：
Bazan, NG