Diverse Brain Myeloid Expression Profiles Reveal Distinct Microglial Activation States and Aspects of Alzheimer's Disease Not Evident in Mouse Models
Diverse Brain Myeloid Expression Profiles Reveal Distinct Microglial Activation States and Aspects of Alzheimer's Disease Not Evident in Mouse Models
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DOI：
10.1016/j.celrep.2017.12.066
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发表时间：
2018-01-16
期刊：
影响因子：
8.8
通讯作者：
Hansen, David V.
中科院分区：
文献类型：
--
作者：
Friedman, Brad A.;Srinivasan, Karpagam;Hansen, David V.
小胶质细胞是驻留于中枢神经系统的免疫细胞，在疾病中发挥着重要作用，但其可能的激活状态的光谱尚不清楚。我们从不同小鼠模型的中枢神经系统髓系细胞的转录图谱中推导出共同调节的基因模块，包括新的直肠病变模型数据集。使用这些模块来解释来自阿尔茨海默病(AD)模型的单细胞数据，我们识别出了小胶质细胞亚群--不同于之前报道的“疾病相关小胶质细胞”--表达干扰素相关或增殖模块。然后，我们分析了人类神经退行性疾病的全组织RNA图谱，包括一个新的AD数据集。纠正了AD组织细胞成分的变化，我们观察到神经退行性变相关模块的表达增加，但也观察到仅使用小鼠模型的表达谱不涉及的模块。我们提供了一个可搜索的交互式数据库，用于探索所有这些数据集(http://research-pub.gene.com/BrainMyeloidLandscape).中的基因表达了解人类疾病中中枢神经系统髓系细胞激活的维度可能会揭示治疗干预的机会。
Microglia, the CNS-resident immune cells, play important roles in disease, but the spectrum of their possible activation states is not well understood. We derived co-regulated gene modules from transcriptional profiles of CNS myeloid cells of diverse mouse models, including new tauopathy model datasets. Using these modules to interpret single-cell data from an Alzheimer's disease (AD) model, we identified microglial subsets-distinct from previously reported "disease-associated microglia''-expressing interferon-related or proliferation modules. We then analyzed whole-tissue RNA profiles from human neurodegenerative diseases, including a new AD dataset. Correcting for altered cellular composition of AD tissue, we observed elevated expression of the neurodegeneration-related modules, but also modules not implicated using expression profiles from mouse models alone. We provide a searchable, interactive database for exploring gene expression in all these datasets (http://research-pub.gene.com/BrainMyeloidLandscape). Understanding the dimensions of CNS myeloid cell activation in human disease may reveal opportunities for therapeutic intervention.