Lack of TREM2 differentially affects the phenotype and transcriptome of mice expressing human APOE3 and APOE4

We aim to investigate the interaction between two of the major genetic risk factors for AD: inheritance of APOEe4 and deficiency of Triggering Receptor Expressed on Myeloid cells 2 (TREM2). Trem2 deletion worsened memory in AD model mice but not in their WT littermates. Interestingly, the lack Trem2 resulted in a significantly less microglia around amyloid plaques in APP mice expressing both APOE isoforms but had no impact on amyloid load. Gene expression analysis identified as Trem2 signature a cluster of highly connected immune response genes, commonly downregulated as a result of Trem2 deletion in all experimental groups, such as Clec7a, Itgax, Cts7, Mpeg1, Csf1r, Cx3cr1, Pik3cg and Spi1/PU.1. In vitro experiments with primary microglia demonstrated a decrease of Abeta phagocytosis in APOE4 versus APOE3 microglia a difference that was augmented by the absence of Trem2. Our data demonstrate that the lack of Trem2 differentially impact the phenotype and brain transcriptome of APP mice expressing human APOE isoforms probably reflecting the difference between APOE isoforms to transport lipids that can affect APOE receptor-binding properties. We crossed 6.5 month old male and female Trem2ko mice with APP/PSEN1dE9 mice expressing human APOE3 or APOE4 isoforms and assessed amyloid pathology, glial response, and whole-brain transcriptome.我们旨在探究阿尔茨海默病（Alzheimer's Disease, AD）两大主要遗传风险因子间的相互作用：载脂蛋白Eε4（APOE ε4）的遗传携带与髓系细胞触发受体2（Triggering Receptor Expressed on Myeloid cells 2, TREM2）的缺陷。 TREM2缺失会加重阿尔茨海默病模型小鼠的记忆损伤，但对其同窝野生型（Wild Type, WT）小鼠无此影响。值得注意的是，在同时表达两种APOE亚型的淀粉样前体蛋白（Amyloid Precursor Protein, APP）模型小鼠中，TREM2缺失会导致淀粉样斑块周围的小胶质细胞数量显著减少，但对淀粉样蛋白负荷无明显影响。 基因表达分析鉴定出一组高度关联的免疫应答基因作为TREM2特征基因集，在所有实验组中，TREM2缺失均会使该基因集普遍下调，例如Clec7a、Itgax、Cts7、Mpeg1、Csf1r、Cx3cr1、Pik3cg及Spi1/PU.1。 原代小胶质细胞体外实验显示，表达APOEε4的小胶质细胞的β淀粉样蛋白（β-Amyloid, Aβ）吞噬能力低于表达APOEε3的小胶质细胞，而TREM2缺失会进一步放大这一差异。 本研究数据表明，TREM2缺失会对表达人源APOE亚型的APP模型小鼠的表型及脑部转录组产生差异化影响，这一现象可能源于APOE亚型在脂质转运能力上的差异，而脂质转运可影响APOE的受体结合特性。 我们将6.5月龄的TREM2敲除（TREM2 knockout, TREM2ko）雌雄小鼠与表达人源APOEε3或APOEε4亚型的APP/PSEN1dE9小鼠进行杂交，并对其淀粉样蛋白病理、胶质细胞应答及全脑转录组进行了评估。