Loss of TREM2 reduces hyperactivation of progranulin deficient microglia but not lysosomal pathology [14 months]

GRN haploinsufficiency causes frontotemporal lobar degeneration and results in microglial hyperactivation, lysosomal dysfunction and TDP-43 deposition. To understand the contribution of microglial hyperactivation to pathology we evaluated genetic and pharmacological approaches suppressing TREM2 dependent transition of microglia from a homeostatic to a disease associated state. Trem2 deficiency in Grn KO mice led to a reduction of microglia activation. To explore antibody-mediated pharmacological modulation of TREM2-dependent microglial states, we identified antagonistic TREM2 antibodies. Treatment of macrophages from GRN-FTLD patients with these antibodies allowed a complete rescue of elevated levels of TREM2 together with increased shedding and reduction of TREM2 signaling. Furthermore, antibody-treated PGRN deficient hiMGL showed dampened microglial hyperactivation, reduced TREM2 signaling and phagocytic activity, however, lack of rescue of lysosomal dysfunction. Similarly, lysosomal dysfunction, lipid dysregulation and glucose hypometabolism of Grn KO mice were not rescued by TREM2 ablation. Furthermore, NfL, a biomarker for neurodegeneration, was elevated in the Grn/Trem2 KO. These findings suggest that microglia hyperactivation is not necessarily contributing to neurotoxicity, and instead demonstrates that TREM2 exhibits neuroprotective potential in this model. In this study we analyzed gene expression in total RNA isolated from whole brain of adult mice. We compared the expression profile of Trem2 knockout mice , Grn knockout mice, and Grn/Trem2 double knockout mice (for each genotype n=3 female, n=3 male, 14 month) to wild type mice (n=3 female, n=3 female, 14 months). Please note that the normalized data for the GSM5617157 - GSM5617168 samples have been updated on Oct 15, 2021.GRN单倍体剂量不足可引发额颞叶变性（frontotemporal lobar degeneration, FTLD），并导致小胶质细胞过度激活、溶酶体功能障碍及TDP-43沉积。为阐明小胶质细胞过度激活对病理进程的贡献，我们评估了抑制髓系细胞触发受体2（TREM2）介导的小胶质细胞从稳态向疾病相关状态转化的遗传与药理学手段。Grn基因敲除（KO）小鼠中Trem2缺失可减轻小胶质细胞活化。为探索抗体介导的TREM2依赖型小胶质细胞状态的药理学调控，我们筛选得到了拮抗性TREM2抗体。用这些抗体处理GRN相关FTLD患者来源的巨噬细胞，可完全恢复异常升高的TREM2水平，同时促进TREM2脱落并降低其信号转导活性。此外，经抗体处理的PGRN缺陷型诱导性小胶质细胞样细胞（hiMGL）表现出小胶质细胞过度激活受抑、TREM2信号转导及吞噬活性降低，但未能改善溶酶体功能障碍。类似地，Grn KO小鼠的溶酶体功能障碍、脂质代谢异常及葡萄糖低代谢均未因Trem2敲除得到逆转。此外，作为神经退行性疾病生物标志物的神经丝轻链（neurofilament light chain, NfL）在Grn/Trem2双敲除小鼠中水平升高。上述研究结果表明，小胶质细胞过度激活未必介导神经毒性，反而提示TREM2在该疾病模型中具有神经保护潜能。本研究分析了成年小鼠全脑提取的总RNA中的基因表达情况，我们将Trem2敲除小鼠、Grn敲除小鼠及Grn/Trem2双敲除小鼠（每种基因型的雌性、雄性小鼠各3只，月龄为14个月）的基因表达谱与野生型小鼠（雌性3只、雌性3只，月龄为14个月）进行了对比。请注意，GSM5617157至GSM5617168样本的标准化数据已于2021年10月15日更新。