Brain macrophage populations include parenchymal microglia, border-associated macrophages, and recruited monocyte-derived cells; together, they control brain development and homeostasis but are also implicated in aging pathogenesis and neurodegeneration. The phenotypes, localization, and functions of each population in different contexts have yet to be resolved. We generated a murine brain myeloid scRNA-seq integration to systematically delineate brain macrophage populations. We show that the previously identified disease-associated microglia (DAM) population detected in murine Alzheimer’s disease models actually comprises two ontogenetically and functionally distinct cell lineages: embryonically derived triggering receptor expressed on myeloid cells 2 (TREM2)-dependent DAM expressing a neuroprotective signature and monocyte-derived TREM2-expressing disease inflammatory macrophages (DIMs) accumulating in the brain during aging. These two distinct populations appear to also be conserved in the human brain. Herein, we generate an ontogeny-resolved model of brain myeloid cell heterogeneity in development, homeostasis, and disease and identify cellular targets for the treatment of neurodegeneration.

脑巨噬细胞群包括实质小胶质细胞、边界相关巨噬细胞和募集的单核细胞衍生细胞；它们共同控制大脑发育和体内平衡，但也与衰老发病机制和神经退化有关。每个群体在不同背景下的表型、定位和功能尚未得到解决。我们生成了鼠脑髓系 scRNA-seq 整合，以系统地描绘脑巨噬细胞群。我们表明，在小鼠阿尔茨海默病模型中检测到的先前确定的疾病相关小胶质细胞 (DAM) 群体实际上包含两个个体遗传学和功能上不同的细胞谱系：胚胎衍生的触发受体表达在骨髓细胞 2 (TREM2) 依赖性 DAM 上，表达神经保护特征和单核细胞衍生的表达 TREM2 的疾病炎性巨噬细胞 (DIM) 在衰老过程中在大脑中积累。这两个不同的种群似乎也保存在人脑中。在这里，我们生成了脑髓细胞在发育、稳态和疾病中的异质性的个体发育解决模型，并确定了用于治疗神经退行性疾病的细胞靶点。