There is currently little information available about how individual cell types contribute to Alzheimer's disease. Here we applied single-nucleus RNA sequencing to entorhinal cortex samples from control and Alzheimer's disease brains (n = 6 per group), yielding a total of 13,214 high-quality nuclei. We detail cell-type-specific gene expression patterns, unveiling how transcriptional changes in specific cell subpopulations are associated with Alzheimer's disease. We report that the Alzheimer's disease risk gene APOE is specifically repressed in Alzheimer's disease oligodendrocyte progenitor cells and astrocyte subpopulations and upregulated in an Alzheimer's disease-specific microglial subopulation. Integrating transcription factor regulatory modules with Alzheimer's disease risk loci revealed drivers of cell-type-specific state transitions towards Alzheimer's disease. For example, transcription factor EB, a master regulator of lysosomal function, regulates multiple disease genes in a specific Alzheimer's disease astrocyte subpopulation. These results provide insights into the coordinated control of Alzheimer's disease risk genes and their cell-type-specific contribution to disease susceptibility. These results are available at http://adsn.ddnetbio.com.

中文翻译：

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阿尔茨海默病患者内嗅皮层的单细胞图谱揭示了细胞类型特异性的基因表达调控。

目前关于单个细胞类型如何导致阿尔茨海默病的信息很少。在这里，我们对来自对照和阿尔茨海默病大脑的内嗅皮层样本（每组 n = 6）应用单核 RNA 测序，总共产生了 13,214 个高质量的细胞核。我们详细描述了细胞类型特异性基因表达模式，揭示了特定细胞亚群的转录变化如何与阿尔茨海默病相关。我们报告称，阿尔茨海默病风险基因 APOE 在阿尔茨海默病少突胶质细胞祖细胞和星形胶质细胞亚群中受到特异性抑制，并在阿尔茨海默病特异性小胶质细胞亚群中上调。将转录因子调控模块与阿尔茨海默病风险基因座整合，揭示了细胞类型特异性状态转变为阿尔茨海默病的驱动因素。例如，转录因子 EB（溶酶体功能的主要调节因子）可调节特定阿尔茨海默病星形胶质细胞亚群中的多种疾病基因。这些结果为阿尔茨海默病风险基因的协调控制及其对疾病易感性的细胞类型特异性贡献提供了见解。这些结果可在 http://adsn.ddnetbio.com 上获取。