TREM2 promotes Aβ phagocytosis by upregulating C/EBPα-dependent CD36 expression in microglia.
TREM2 promotes Aβ phagocytosis by upregulating C/EBPα-dependent CD36 expression in microglia.
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DOI：
10.1038/s41598-017-11634-x
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发表时间：
2017-09-11
影响因子：
4.6
通讯作者：
Kang HS
中科院分区：
文献类型：
--
作者：
Kim SM;Mun BR;Lee SJ;Joh Y;Lee HY;Ji KY;Choi HR;Lee EH;Kim EM;Jang JH;Song HW;Mook-Jung I;Choi WS;Kang HS
TREM2通过促进小胶质细胞对Aβ的吞噬作用在缓解阿尔茨海默病中发挥着关键作用，但TREM2诱导Aβ直接吞噬活性的详细分子机制仍有待揭示。我们发现老年 TREM2 TG 小鼠的学习和记忆功能得到改善，而 KO 小鼠的效果则相反。 KO 小鼠的原代小胶质细胞中被吞噬的 Aβ 数量显着减少。 TG 小鼠中原代小胶质细胞中 CD36 的表达高于 WT 小鼠，但 KO 小鼠中的表达显着降低。 C/EBPα（CD36 的上游转录激活因子）的表达在 TG 小鼠的原代小胶质细胞中也升高，但在 KO 小鼠中降低。 TREM2 过表达使 CD36 的转录显着增加，并且这种效应被 CD36 启动子上的 C/EBPα 结合位点的突变所抑制。 TREM2 诱导的 CD36 和 C/EBPα 表达可通过 PI3K/AKT 信号阻断剂处理得到抑制，并且在 TREM2 过表达的 BV2 细胞中 AKT 磷酸化升高。本研究提供的证据表明，TREM2 通过调节 C/EBPα 依赖性 CD36 表达和随之而来的 Aβ 吞噬作用来预防阿尔茨海默病中的记忆和学习丧失。
TREM2 plays a critical role in the alleviation of Alzheimer’s disease by promoting Aβ phagocytosis by microglia, but the detailed molecular mechanism underlying TREM2-induced direct phagocytic activity of Aβ remains to be revealed. We found that learning and memory functions were improved in aged TREM2 TG mice, with the opposite effects in KO mice. The amount of phagocytosed Aβ was significantly reduced in the primary microglia of KO mice. CD36 expression in primary microglia was greater in TG than in WT mice but was substantially decreased in KO mice. The expression of C/EBPα, an upstream transcriptional activator of CD36, was also elevated in primary microglia of TG mice but decreased in KO mice. The transcription of CD36 was markedly increased by TREM2 overexpression, and this effect was suppressed by a mutation of the C/EBPα binding site on the CD36 promoter. The TREM2-induced expression of CD36 and C/EBPα was inhibited by treatment with PI3K/AKT signaling blockers, and phosphorylation of AKT was elevated in TREM2-overexpressing BV2 cells. The present study provides evidence that TREM2 is required for preventing loss of memory and learning in Alzheimer’s disease by regulating C/EBPα-dependent CD36 expression and the consequent Aβ phagocytosis.
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影响因子：
5.1
作者：
Fu, Ruying;Shen, Qingyu;Xu, Pengfei;Luo, Jin Jun;Tang, Yamei
通讯作者：
Tang, Yamei
CD36介导了对β-淀粉样蛋白的先天宿主反应。
影响因子：
15.3
作者：
El Khoury, JB;Moore, KJ;Means, TK;Leung, J;Terada, K;Toft, M;Freeman, MW;Luster, AD
通讯作者：
Luster, AD
影响因子：
7.3
作者：
Peng Q;Malhotra S;Torchia JA;Kerr WG;Coggeshall KM;Humphrey MB
通讯作者：
Humphrey MB
影响因子：
3.7
作者：
Kittelberger KA;Piazza F;Tesco G;Reijmers LG
通讯作者：
Reijmers LG
影响因子：
64.5
作者：
Huang Y;Mucke L
通讯作者：
Mucke L