Institute of Neuronal Cell Biology, Technical University Munich, 80802 Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany.
Institute for Stroke and Dementia Research, University Hospital of Munich, LMU Munich, 81377 Munich, Germany.
Neuron. 2021 Apr 7;109(7):1100-1117.e10. doi: 10.1016/j.neuron.2021.01.027. Epub 2021 Feb 18.
Aging results in gray and white matter degeneration, but the specific microglial responses are unknown. Using single-cell RNA sequencing from white and gray matter separately, we identified white matter-associated microglia (WAMs), which share parts of the disease-associated microglia (DAM) gene signature and are characterized by activation of genes implicated in phagocytic activity and lipid metabolism. WAMs depend on triggering receptor expressed on myeloid cells 2 (TREM2) signaling and are aging dependent. In the aged brain, WAMs form independent of apolipoprotein E (APOE), in contrast to mouse models of Alzheimer's disease, in which microglia with the WAM gene signature are generated prematurely and in an APOE-dependent pathway similar to DAMs. Within the white matter, microglia frequently cluster in nodules, where they are engaged in clearing degenerated myelin. Thus, WAMs may represent a potentially protective response required to clear degenerated myelin accumulating during white matter aging and disease.
衰老是导致灰质和白质退化的原因，但具体的小胶质细胞反应尚不清楚。我们使用分别来自白质和灰质的单细胞 RNA 测序，鉴定出了与白质相关的小胶质细胞（WAMs），它们共享部分与疾病相关的小胶质细胞（DAM）基因特征，并表现出参与吞噬活性和脂质代谢的基因激活。WAMs 依赖于髓样细胞表达的触发受体 2（TREM2）信号，并且与衰老有关。在衰老的大脑中，WAMs 的形成不依赖于载脂蛋白 E（APOE），与阿尔茨海默病的小鼠模型形成鲜明对比，在该模型中，具有 WAM 基因特征的小胶质细胞过早产生，并且依赖于与 DAM 相似的 APOE 途径。在白质内，小胶质细胞经常在结节中聚集，在那里它们参与清除退化的髓鞘。因此，WAMs 可能代表一种潜在的保护反应，需要清除在白质衰老和疾病过程中积累的退化的髓鞘。
