Alzheimer’s disease (AD) is a complex neurodegenerative disease, perturbing neuronal and non-neuronal cell populations. In this study, using single-cell transcriptomics, we mapped all non-immune, non-neuronal cell populations in wild-type and AD model (5xFAD) mouse brains. We identified an oligodendrocyte state that increased in association with brain pathology, which we termed disease-associated oligodendrocytes (DOLs). In a murine model of amyloidosis, DOLs appear long after plaque accumulation, and amyloid-beta (Aβ) alone was not sufficient to induce the DOL signature in vitro. DOLs could be identified in a mouse model of tauopathy and in other murine neurodegenerative and autoimmune inflammatory conditions, suggesting a common response to severe pathological conditions. Using quantitative spatial analysis of mouse and postmortem human brain tissues, we found that oligodendrocytes expressing a key DOL marker (SERPINA3N/SERPINA3 accordingly) are present in the cortex in areas of brain damage and are enriched near Aβ plaques. In postmortem human brain tissue, the expression level of this marker correlated with cognitive decline. Altogether, this study uncovers a shared signature of oligodendrocytes in central nervous system pathologies.

阿尔茨海默病 (AD) 是一种复杂的神经退行性疾病，扰乱神经元和非神经元细胞群。在这项研究中，我们使用单细胞转录组学绘制了野生型和 AD 模型 (5xFAD) 小鼠大脑中的所有非免疫、非神经元细胞群。我们确定了一种与脑病理相关的少突胶质细胞状态，我们将其称为疾病相关少突胶质细胞 (DOL)。在淀粉样变性小鼠模型中，DOL 在斑块积聚后很长时间出现，而单独的淀粉样蛋白 (Aβ) 不足以在体外诱导 DOL 特征。DOLs 可以在 tau 病小鼠模型和其他小鼠神经退行性和自身免疫性炎症条件下被识别，表明对严重病理条件的共同反应。通过对小鼠和死后人脑组织进行定量空间分析，我们发现表达关键 DOL 标记（相应的 SERPINA3N/SERPINA3）的少突胶质细胞存在于脑损伤区域的皮质中，并且在 Aβ 斑块附近富集。在死后的人脑组织中，该标记物的表达水平与认知能力下降相关。总而言之，这项研究揭示了少突胶质细胞在中枢神经系统病理学中的共同特征。