Triggering receptor expressed on myeloid cells 2 (TREM2) sustains microglia response to brain injury stimuli including apoptotic cells, myelin damage, and amyloid β (Aβ). Alzheimer’s disease (AD) risk is associated with the TREM2^R47H variant, which impairs ligand binding and consequently microglia responses to Aβ pathology. Here, we show that TREM2 engagement by the mAb hT2AB as surrogate ligand activates microglia in 5XFAD transgenic mice that accumulate Aβ and express either the common TREM2 variant (TREM2^CV) or TREM2^R47H. scRNA-seq of microglia from TREM2^CV-5XFAD mice treated once with control hIgG1 exposed four distinct trajectories of microglia activation leading to disease-associated (DAM), interferon-responsive (IFN-R), cycling (Cyc-M), and MHC-II expressing (MHC-II) microglia types. All of these were underrepresented in TREM2^R47H-5XFAD mice, suggesting that TREM2 ligand engagement is required for microglia activation trajectories. Moreover, Cyc-M and IFN-R microglia were more abundant in female than male TREM2^CV-5XFAD mice, likely due to greater Aβ load in female 5XFAD mice. A single systemic injection of hT2AB replenished Cyc-M, IFN-R, and MHC-II pools in TREM2^R47H-5XFAD mice. In TREM2^CV-5XFAD mice, however, hT2AB brought the representation of male Cyc-M and IFN-R microglia closer to that of females, in which these trajectories had already reached maximum capacity. Moreover, hT2AB induced shifts in gene expression patterns in all microglial pools without affecting representation. Repeated treatment with a murinized hT2AB version over 10 d increased chemokines brain content in TREM2^R47H-5XFAD mice, consistent with microglia expansion. Thus, the impact of hT2AB on microglia is shaped by the extent of TREM2 endogenous ligand engagement and basal microglia activation.

髓样细胞 2 (TREM2) 上表达的触发受体维持小胶质细胞对脑损伤刺激的反应，包括细胞凋亡、髓磷脂损伤和 β 淀粉样蛋白 (Aβ)。阿尔茨海默病 (AD) 风险与TREM2 ^R47H变异相关，该变异会损害配体结合，从而损害小胶质细胞对 Aβ 病理学的反应。在这里，我们发现 mAb hT2AB 作为替代配体与 TREM2 结合可激活 5XFAD 转基因小鼠中的小胶质细胞，这些小鼠积累 ​​Aβ 并表达常见的 TREM2 变体 ( TREM2 ^CV ) 或TREM2 ^R47H 。用对照 hIgG1 处理一次的TREM2 ^CV -5XFAD 小鼠的小胶质细胞的 scRNA-seq 暴露出四种不同的小胶质细胞激活轨迹，导致疾病相关 (DAM)、干扰素响应 (IFN-R)、循环 (Cyc-M) 和 MHC -II 表达 (MHC-II) 小胶质细胞类型。所有这些在TREM2 ^R47H -5XFAD 小鼠中均未得到充分体现，表明 TREM2 配体参与是小胶质细胞激活轨迹所必需的。此外，雌性TREM2 CV -5XFAD 小鼠中的 Cyc-M 和 IFN-R 小胶质细胞比雄性 TREM2 ^CV -5XFAD 小鼠更丰富，这可能是由于雌性 5XFAD 小鼠中 Aβ 负载更大。单次全身注射 hT2AB 可以补充TREM2 ^R47H -5XFAD 小鼠的 Cyc-M、IFN-R 和 MHC-II 池。然而，在TREM2 ^CV -5XFAD 小鼠中，hT2AB 使雄性 Cyc-M 和 IFN-R 小胶质细胞的表现更接近雌性，其中这些轨迹已经达到最大容量。此外，hT2AB 诱导所有小胶质细胞池中基因表达模式的变化，而不影响代表性。 使用鼠源化 hT2AB 版本重复治疗 10 天以上，增加了TREM2 ^R47H -5XFAD 小鼠脑中趋化因子的含量，这与小胶质细胞的扩张一致。因此，hT2AB 对小胶质细胞的影响是由 TREM2 内源配体接合和基底小胶质细胞激活的程度决定的。