A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease
A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease
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DOI：
10.1016/j.cell.2017.05.018
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发表时间：
2017-06-15
期刊：
影响因子：
64.5
通讯作者：
Amit, Ido
中科院分区：
文献类型：
--
作者：
Keren-Shaul, Hadas;Spinrad, Amit;Amit, Ido
阿尔茨海默病（AD）是一种有害的神经退行性疾病，没有有效的治疗方法。由于细胞异质性，确定免疫细胞亚群在AD发病和进展中的作用一直是一个挑战。使用转录单细胞分选，我们全面映射野生型和AD转基因（Tg-AD）小鼠脑中的所有免疫群体。我们描述了一种与神经退行性疾病（DAM）相关的新型小胶质细胞，并鉴定了与这些细胞相关的标记物、空间定位和通路。小鼠和人脑切片的免疫组织化学染色显示具有细胞内/吞噬A β颗粒的DAM。Tg-AD中DAM和髓样细胞2（Trem 2）（-/-）Tg-AD上表达的触发受体的单细胞分析揭示DAM程序在两步过程中被激活。激活以Trem 2非依赖性方式启动，涉及小胶质细胞检查点的下调，然后激活Trem 2依赖性程序。这种独特的小胶质细胞类型具有限制神经退行性变的潜力，这可能对AD和其他神经退行性疾病的未来治疗具有重要意义。
Alzheimer's disease (AD) is a detrimental neurodegenerative disease with no effective treatments. Due to cellular heterogeneity, defining the roles of immune cell subsets in AD onset and progression has been challenging. Using transcriptional single-cell sorting, we comprehensively map all immune populations in wild-type and AD-transgenic (Tg-AD) mouse brains. We describe a novel microglia type associated with neurodegenerative diseases (DAM) and identify markers, spatial localization, and pathways associated with these cells. Immunohistochemical staining of mice and human brain slices shows DAM with intracellular/phagocytic A beta particles. Single-cell analysis of DAM in Tg-AD and triggering receptor expressed on myeloid cells 2 (Trem2)(-/-) Tg-AD reveals that the DAM program is activated in a two-step process. Activation is initiated in a Trem2-independent manner that involves downregulation of microglia checkpoints, followed by activation of a Trem2-dependent program. This unique microglia-type has the potential to restrict neurodegeneration, which may have important implications for future treatment of AD and other neurodegenerative diseases.