澳大利亚莫纳什大学Jose M. Polo、新加坡国立大学医学院Enrico Petretto和Owen J. L. Rackham课题组合作，通过绘制阿尔兹海默症患者内嗅皮层单细胞图谱，揭示了特异细胞类型基因的表达调控。11月25日，《自然—神经科学》在线发表了这一成果。

研究人员利用单核RNA测序对来自正常人和阿尔兹海默症患者的脑内嗅皮层样本（每组n = 6）进行测序，共产生了13,214个高质量测序本。研究人员详细描绘了细胞类型特定的基因表达模式，揭示了特定细胞亚群中的转录变化与阿尔兹海默症的关系。

研究人员发现阿尔兹海默症的疾病风险基因APOE在阿尔兹海默症的少突胶质细胞祖细胞和星形胶质细胞亚群中被特异性抑制，而在阿尔兹海默症患者特异的小胶质细胞亚群中被上调。

通过将转录因子调节模式与阿尔兹海默症风险位点整合后，研究人员发现特定细胞类型向阿尔茨海默病转变的驱动力。例如，在阿尔兹海默症患者特异性的星形胶质细胞亚群中，转录因子EB（其主要调节溶酶体功能）调控多种疾病基因。

该研究有助于人们理解阿尔兹海默症风险基因的协调调控以及特定细胞类型对阿尔兹海默症发生的影响。这些结果可从http://adsn.ddnetbio.com获得。

研究人员表示，目前，关于单类细胞如何导致阿尔兹海默症的信息很少。

附：英文原文

Title: A single-cell atlas of entorhinal cortex from individuals with Alzheimer’s disease reveals cell-type-specific gene expression regulation

Author: Alexandra Grubman, Gabriel Chew, John F. Ouyang, Guizhi Sun, Xin Yi Choo, Catriona McLean, Rebecca K. Simmons, Sam Buckberry, Dulce B. Vargas-Landin, Daniel Poppe, Jahnvi Pflueger, Ryan Lister, Owen J. L. Rackham, Enrico Petretto, Jose M. Polo

Issue&Volume: 2019-11-25

Abstract: 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.

DOI: 10.1038/s41593-019-0539-4

Source: https://www.nature.com/articles/s41593-019-0539-4