Jendresen Charlotte, Årskog Vibeke, Daws Michael R, Nilsson Lars N G
Department of Pharmacology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Postboks 1057 Blindern, 0316, Oslo, Norway.
Division of Anatomy, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
J Neuroinflammation. 2017 Mar 21;14(1):59. doi: 10.1186/s12974-017-0835-4.
Triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (APOE) are genetically linked to Alzheimer's disease. Here, we investigated whether human ApoE mediates signal transduction through human and murine TREM2 and sought to identify a TREM2-binding domain in human ApoE.
To investigate cell signaling through TREM2, a cell line was used which expressed an NFAT-inducible β-galactosidase reporter and human or murine TREM2, fused to CD8 transmembrane and CD3ζ intracellular signaling domains. ELISA-based binding assays were used to determine binding affinities of human ApoE isoforms to human TREM2 and to identify a TREM2-binding domain in ApoE.
ApoE was found to be an agonist to human TREM2 with EC in the low nM range, and to murine TREM2 with reduced potency. In the reporter cells, TREM2 expression was lower than in nontransgenic mouse brain. Human ApoE isoforms ε2, ε3, and ε4 bound to human TREM2 with K in the low nM range. The binding was displaced by an ApoE-mimetic peptide (amino acids 130-149).
An ApoE-mediated dose-dependent signal transduction through TREM2 in reporter cells was demonstrated, and a TREM2-binding region in ApoE was identified. The relevance of an ApoE-TREM2 receptor signaling pathway to Alzheimer's disease is discussed.
髓系细胞触发受体2（TREM2）和载脂蛋白E（APOE）在基因上与阿尔茨海默病相关。在此，我们研究了人类载脂蛋白E是否通过人类和小鼠TREM2介导信号转导，并试图在人类载脂蛋白E中鉴定出TREM2结合域。
为研究通过TREM2的细胞信号传导，使用了一种表达NFAT诱导型β-半乳糖苷酶报告基因以及与CD8跨膜和CD3ζ细胞内信号域融合的人类或小鼠TREM2的细胞系。基于酶联免疫吸附测定（ELISA）的结合试验用于确定人类载脂蛋白E异构体与人类TREM2的结合亲和力，并在载脂蛋白E中鉴定TREM2结合域。
发现载脂蛋白E是人类TREM2的激动剂，其半数有效浓度（EC）在低纳摩尔范围内，对小鼠TREM2的效力较低。在报告细胞中，TREM2的表达低于非转基因小鼠脑内。人类载脂蛋白E异构体ε2、ε3和ε4与人类TREM2结合，解离常数（K）在低纳摩尔范围内。该结合被一种载脂蛋白E模拟肽（氨基酸130 - 149）取代。
在报告细胞中证实了载脂蛋白E通过TREM2介导剂量依赖性信号转导，并鉴定出载脂蛋白E中的TREM2结合区域。讨论了载脂蛋白E - TREM2受体信号通路与阿尔茨海默病的相关性。
