TREM2 regulates microglial cholesterol metabolism upon chronic phagocytic challenge [bulk RNA-seq]

TREM2 is a microglial-specific gene implicated in late-onset Alzheimer's Disease (AD). Recent studies have identified that Trem2-deficient mice exhibit transcriptional changes in microglial gene expression that minimize the upregulation of lipid metabolism and lysosomal genes in AD disease models. We find that chronic phagocytic challenge from demyelination generates similiarly attenuated expression of lysosomal and lipid metabolism genes in microglia isolated from Trem2 knockout mouse brain. Trem2 wildtype, heterozyogus knockout, and homozygous knockout mice were fed a control or 0.2% cuprizone diet for 5 weeks or 12 weeks to generate acute or chronic demyelination, respectively. Microglial and pooled non-microglial cell type gene expression was assessed using 3' tag sequencing of poly-adenylated RNA (QuantSeq, Lexogen, Vienna, Austria).TREM2是一种小胶质细胞（microglia）特异性基因，与迟发性阿尔茨海默病（AD）存在关联。近期研究证实，在AD疾病模型中，Trem2缺陷小鼠的小胶质细胞基因表达会出现转录组改变，从而抑制脂质代谢与溶酶体（lysosome）相关基因的上调表达。本研究发现，脱髓鞘引发的慢性吞噬应激，会使从Trem2敲除小鼠脑组织中分离的小胶质细胞，同样表现出溶酶体与脂质代谢基因的表达下调。我们将Trem2野生型、杂合敲除及纯合敲除小鼠分为对照组与0.2% cuprizone（双环己酮草酰二腙）饮食组，分别饲喂5周与12周，以构建急性与慢性脱髓鞘模型。本研究通过聚腺苷酸化RNA的3'端标签测序技术（QuantSeq，Lexogen，奥地利维也纳），对小胶质细胞及混合非小胶质细胞群的基因表达水平进行了检测。