研究人员对阿兹海默病进行了单细胞转录组分析，从而为找到新型潜在药物靶点提供可能。这一成果由麻省理工学院Li-Huei Tsai团队和Manolis Kellis团队取得。该研究成果于2019年6月20日发表在国际顶尖学术期刊《自然》上。

课题组人员分析了来自48名不同程度阿尔茨海默病病理患者前额皮质的80660个单核转录组。在6种主要的脑细胞类型中，研究人员确定了不同的转录组亚群，包括那些与病理相关的亚群，并以髓鞘形成、炎症和神经元存活的调节因子为特征。与疾病相关的最强变化出现在病理进展的早期，且具有高度的细胞类型特异性，然而在晚期，不同的细胞类型中呈现出相似的基因上调，主要是参与应激反应的基因。值得注意的是，研究发现，在与疾病相关的亚群中，女性细胞的比例过高，而且在包括少突胶质细胞在内的几种细胞类型中，转录反应在性别间存在显著差异。总体而言，髓鞘形成相关过程在多种细胞类型中反复受到干扰，这表明髓鞘形成在阿尔茨海默病病理生理学中具有关键作用。他们的单细胞转录组资源为研究阿尔茨海默病的分子和细胞基础提供了蓝图。

据了解，阿尔茨海默病是一种广泛性的神经退行性疾病，调控其的分子及机制较复杂，至今仍不为人所知。

附：英文原文

Title: Single-cell transcriptomic analysis of Alzheimer’s disease

Author: Hansruedi Mathys, Jose Davila-Velderrain, Zhuyu Peng, Fan Gao, Shahin Mohammadi, Jennie Z. Young, Madhvi Menon, Liang He, Fatema Abdurrob, Xueqiao Jiang, Anthony J. Martorell, Richard M. Ransohoff, Brian P. Hafler, David A. Bennett, Manolis Kellis, Li-Huei Tsai

Issue&Volume: Volume 570 Issue 7761, 20 June 2019

Abstract: Alzheimers disease is a pervasive neurodegenerative disorder, the molecular complexity of which remains poorly understood. Here, we analysed 80,660 single-nucleus transcriptomes from the prefrontal cortex of 48 individuals with varying degrees of Alzheimers disease pathology. Across six major brain cell types, we identified transcriptionally distinct subpopulations, including those associated with pathology and characterized by regulators of myelination, inflammation, and neuron survival. The strongest disease-associated changes appeared early in pathological progression and were highly cell-type specific, whereas genes upregulated at late stages were common across cell types and primarily involved in the global stress response. Notably, we found that female cells were overrepresented in disease-associated subpopulations, and that transcriptional responses were substantially different between sexes in several cell types, including oligodendrocytes. Overall, myelination-related processes were recurrently perturbed in multiple cell types, suggesting that myelination has a key role in Alzheimers disease pathophysiology. Our single-cell transcriptomic resource provides a blueprint for interrogating the molecular and cellular basis of Alzheimers disease.

DOI: 10.1038/s41586-019-1195-2

Source:https://www.nature.com/articles/s41586-019-1195-2