Triggering receptor expressed on myeloid cells 2 (TREM2) is essential for the transition of homeostatic microglia to a disease-associated microglial state. To enhance TREM2 activity, we sought to selectively increase the full-length protein on the cell surface via reducing its proteolytic shedding by A Disintegrin And Metalloproteinase (i.e., α-secretase) 10/17. We screened a panel of monoclonal antibodies against TREM2, with the aim to selectively compete for α-secretase-mediated shedding. Monoclonal antibody 4D9, which has a stalk region epitope close to the cleavage site, demonstrated dual mechanisms of action by stabilizing TREM2 on the cell surface and reducing its shedding, and concomitantly activating phospho-SYK signaling. 4D9 stimulated survival of macrophages and increased microglial uptake of myelin debris and amyloid β-peptide in vitro. In vivo target engagement was demonstrated in cerebrospinal fluid, where nearly all soluble TREM2 was 4D9-bound. Moreover, in a mouse model for Alzheimer's disease-related pathology, 4D9 reduced amyloidogenesis, enhanced microglial TREM2 expression, and reduced a homeostatic marker, suggesting a protective function by driving microglia toward a disease-associated state.

中文翻译：

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用对茎区域的双重功能TREM2抗体增强保护性小胶质细胞活性。

骨髓细胞2（TREM2）上表达的触发受体对于稳态小胶质细胞向疾病相关的小胶质细胞状态的转化至关重要。为了增强TREM2活性，我们试图通过减少Disintegrin和金属蛋白酶（即α-分泌酶）10/17的蛋白水解作用来选择性增加细胞表面的全长蛋白。我们筛选了一组针对TREM2的单克隆抗体，目的是选择性竞争α-分泌酶介导的脱落。具有靠近切割位点的茎区域表位的单克隆抗体4D9通过稳定细胞表面上的TREM2并减少其脱落并同时激活磷酸-SYK信号传导，展示了双重作用机制。4D9刺激巨噬细胞的存活，并在体外增加髓磷脂碎片和淀粉样β肽对小胶质细胞的吸收。在脑脊液中证实了体内靶标结合，其中几乎所有可溶性TREM2都被4D9结合。此外，在阿尔茨海默氏病相关病理的小鼠模型中，4D9减少了淀粉样蛋白的生成，增强了小胶质TREM2的表达，并减少了体内稳态的标志物，提示通过将小胶质细胞推向疾病相关状态来发挥保护作用。