Human genetics and preclinical studies have identified key contributions of TREM2 to several neurodegenerative conditions, inspiring efforts to modulate TREM2 therapeutically. Here, we characterize the activities of three TREM2 agonist antibodies in multiple mixed-sex mouse models of Alzheimer's disease (AD) pathology and remyelination. Receptor activation and downstream signaling are explored in vitro, and active dose ranges are determined in vivo based on pharmacodynamic responses from microglia. For mice bearing amyloid-β (Aβ) pathology (PS2APP) or combined Aβ and tau pathology (TauPS2APP), chronic TREM2 agonist antibody treatment had limited impact on microglia engagement with pathology, overall pathology burden, or downstream neuronal damage. For mice with demyelinating injuries triggered acutely with lysolecithin, TREM2 agonist antibodies unexpectedly disrupted injury resolution. Likewise, TREM2 agonist antibodies limited myelin recovery for mice experiencing chronic demyelination from cuprizone. We highlight the contributions of dose timing and frequency across models. These results introduce important considerations for future TREM2-targeting approaches.

人类遗传学和临床前研究已经确定了 TREM2 对多种神经退行性疾病的关键作用，激发了人们在治疗上调节 TREM2 的努力。在这里，我们表征了三种 TREM2 激动剂抗体在阿尔茨海默病 (AD) 病理学和髓鞘再生的多个混合性别小鼠模型中的活性。在体外探索受体激活和下游信号传导，并根据小胶质细胞的药效反应确定体内活性剂量范围。对于患有淀粉样蛋白-β (Aβ) 病理学 (PS2APP) 或 Aβ 和 tau 蛋白联合病理学 (TauPS2APP) 的小鼠，长期 TREM2 激动剂抗体治疗对小胶质细胞与病理学的参与、总体病理学负担或下游神经元损伤的影响有限。对于溶血卵磷脂急性引发脱髓鞘损伤的小鼠，TREM2 激动剂抗体出乎意料地破坏了损伤的消退。同样，TREM2 激动剂抗体限制了因铜宗导致慢性脱髓鞘的小鼠的髓磷脂恢复。我们强调了不同模型中剂量时机和频率的贡献。这些结果为未来 TREM2 靶向方法引入了重要的考虑因素。