Microglia are central players in Alzheimer’s disease pathology but analyzing microglial states in human brain samples is challenging due to genetic diversity, postmortem delay and admixture of pathologies. To circumvent these issues, here we generated 138,577 single-cell expression profiles of human stem cell-derived microglia xenotransplanted in the brain of the App^NL-G-F model of amyloid pathology and wild-type controls. Xenografted human microglia adopt a disease-associated profile similar to that seen in mouse microglia, but display a more pronounced human leukocyte antigen or HLA state, likely related to antigen presentation in response to amyloid plaques. The human microglial response also involves a pro-inflammatory cytokine/chemokine cytokine response microglia or CRM response to oligomeric Aβ oligomers. Genetic deletion of TREM2 or APOE as well as APOE polymorphisms and TREM2^R47H expression in the transplanted microglia modulate these responses differentially. The expression of other Alzheimer’s disease risk genes is differentially regulated across the distinct cell states elicited in response to amyloid pathology. Thus, we have identified multiple transcriptomic cell states adopted by human microglia in a multipronged response to Alzheimer’s disease-related pathology, which should be taken into account in translational studies.

小胶质细胞是阿尔茨海默病病理学的核心参与者，但由于遗传多样性、死后延迟和病理混合，分析人脑样本中的小胶质细胞状态具有挑战性。为了规避这些问题，我们在这里生成了 138,577 个人类干细胞来源的小胶质细胞异种移植到淀粉样蛋白病理学App ^NL-GF模型和野生型对照大脑中的单细胞表达谱。异种移植的人类小胶质细胞采用与小鼠小胶质细胞相似的疾病相关特征，但表现出更明显的人类白细胞抗原或 HLA 状态，可能与响应淀粉样斑块的抗原呈递有关。人小胶质细胞反应还涉及促炎细胞因子/趋化因子细胞因子反应小胶质细胞或对寡聚 Aβ 寡聚物的 CRM 反应。TREM2或APOE的基因缺失以及APOE多态性和移植小胶质细胞中TREM2 ^R47H的表达以不同方式调节这些反应。其他阿尔茨海默病风险基因的表达在淀粉样蛋白病理引起的不同细胞状态中受到差异性调节。因此，我们已经确定了人类小胶质细胞在对阿尔茨海默病相关病理学的多方面反应中采用的多种转录组细胞状态，这在转化研究中应该考虑在内。