The R47H variant in the microglial TREM2 receptor is a strong risk factor for Alzheimer's disease (AD). To characterize processes affected by R47H we performed integrative network analysis of genes expressed in brains of AD patients with R47H, sporadic AD without the variant and patients with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), a systemic disease with early onset dementia caused by loss-of function mutations in TREM2 or its adaptor TYROBP. While sporadic AD had few perturbed microglial and immune genes, TREM2 R47H AD demonstrated upregulation of interferon type I response and pro-inflammatory cytokines accompanied by induction of NKG2D stress ligands. In contrast, PLOSL had distinct sets of highly perturbed immune and microglial genes that included inflammatory mediators, immune signaling, cell adhesion and phagocytosis. TREM2 knock-out in THP1, a human myeloid cell line that constitutively expresses the TREM2-TYROBP receptor, inhibited response to the viral RNA mimetic poly(I:C), and overexpression of ectopic TREM2 restored the response. Compared to wild type protein, R47H TREM2 had higher stimulatory effect on the interferon type I response signature. Our findings point to a role of the TREM2 receptor in the control of the interferon type I response in myeloid cells and provide insight regarding the contribution of R47H TREM2 to AD pathology.

中文翻译：

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TREM2 R47H加剧阿尔茨海默氏病大脑的免疫反应

小胶质TREM2受体中的R47H变体是阿尔茨海默氏病（AD）的重要危险因素。为了表征受R47H影响的过程，我们对R47H，散发性AD无变异的AD患者和多囊性脂质膜性骨质增生伴有硬化性白质脑病（PLOSL）的患者的大脑进行了基因表达网络的综合分析，该疾病是由丢失引起的早期痴呆-在TREM2或其衔接子TYROBP中的功能突变。尽管偶发性AD几乎没有扰动的小胶质细胞和免疫基因，但TREM2 R47H AD表现出I型干扰素应答和促炎性细胞因子的上调，并伴有NKG2D应激配体的诱导。相比之下，PLOSL具有高度扰动的免疫和小神经胶质基因的不同集合，其中包括炎症介质，免疫信号，细胞粘附和吞噬作用。THP1中的TREM2敲除是一种人类髓样细胞系，其组成性表达TREM2-TYROBP受体，抑制了对病毒RNA模仿的poly（I：C）的应答，而异位TREM2的过表达恢复了应答。与野生型蛋白相比，R47H TREM2对I型干扰素应答信号具有更高的刺激作用。我们的发现指出TREM2受体在控制髓样细胞中I型干扰素应答中的作用，并提供有关R47H TREM2对AD病理学贡献的见解。R47H TREM2对I型干扰素反应信号具有更高的刺激作用。我们的发现指出TREM2受体在控制髓样细胞中I型干扰素应答中的作用，并提供有关R47H TREM2对AD病理学贡献的见解。R47H TREM2对I型干扰素反应信号具有更高的刺激作用。我们的发现指出了TREM2受体在控制髓样细胞中I型干扰素应答中的作用，并提供了有关R47H TREM2对AD病理学贡献的见解。