小柯机器人

美国麻省理工学院和哈佛大学布罗德研究所Manolis Kellis和Li-Huei Tsai共同合作，近期取得重要工作进展。他们对阿尔茨海默病患者脑血管系统进行了单核多区转录组学分析。相关研究成果2023年6月1日在线发表于《自然—神经科学》杂志上。

据介绍，脑血管失调是阿尔茨海默病（AD）的标志，但发生在特定细胞类型中的变化尚未完全表征。

研究人员对220名AD患者和208名年龄匹配的对照组人群六个大脑区域的人类脑血管系统中的单核转录组数据进行了分析。研究人员注释了22514个脑血管细胞，包括内皮细胞、周细胞、平滑肌细胞、血管周围成纤维细胞和室管膜细胞的11个亚型。研究人员鉴定了2676个在AD中差异表达的基因，包括周细胞中PDGFRB的下调，以及内皮细胞中ABCB1和ATP10A的下调，并验证了死后AD脑组织中SLC6A1的下调以及APOD、INSR和COL4A1的上调。研究人员检测到血管系统、神经胶质和神经元共表达的基因模块，表明AD中存在协调的神经血管单元失调。与AD遗传学的整合显示125个AD差异表达基因与AD相关的遗传变异直接相关。

最后，研究人员发现APOE4基因型相关差异在毛细血管和小静脉内皮细胞以及周细胞和成纤维细胞亚群中的AD相关基因中显著富集。

附：英文原文

Title: Single-nucleus multiregion transcriptomic analysis of brain vasculature in Alzheimer’s disease

Author: Sun, Na, Akay, Leyla Anne, Murdock, Mitchell H., Park, Yongjin, Galiana-Melendez, Fabiola, Bubnys, Adele, Galani, Kyriaki, Mathys, Hansruedi, Jiang, Xueqiao, Ng, Ayesha P., Bennett, David A., Tsai, Li-Huei, Kellis, Manolis

Issue&Volume: 2023-06-01

Abstract: Cerebrovascular dysregulation is a hallmark of Alzheimer’s disease (AD), but the changes that occur in specific cell types have not been fully characterized. Here, we profile single-nucleus transcriptomes in the human cerebrovasculature in six brain regions from 220 individuals with AD and 208 age-matched controls. We annotate 22,514 cerebrovascular cells, including 11 subtypes of endothelial, pericyte, smooth muscle, perivascular fibroblast and ependymal cells. We identify 2,676 differentially expressed genes in AD, including downregulation of PDGFRB in pericytes, and of ABCB1 and ATP10A in endothelial cells, and validate the downregulation of SLC6A1 and upregulation of APOD, INSR and COL4A1 in postmortem AD brain tissues. We detect vasculature, glial and neuronal coexpressed gene modules, suggesting coordinated neurovascular unit dysregulation in AD. Integration with AD genetics reveals 125 AD differentially expressed genes directly linked to AD-associated genetic variants. Lastly, we show that APOE4 genotype-associated differences are significantly enriched among AD-associated genes in capillary and venule endothelial cells, as well as subsets of pericytes and fibroblasts.

DOI: 10.1038/s41593-023-01334-3

Source: https://www.nature.com/articles/s41593-023-01334-3

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex