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阿尔茨海默病大脑血管的单细胞多区域转录组分析。

Single-nucleus multiregion transcriptomic analysis of brain vasculature in Alzheimer's disease.

机构信息

MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA, USA.

Broad Institute of MIT and Harvard, Cambridge, MA, USA.

出版信息

Nat Neurosci. 2023 Jun;26(6):970-982. doi: 10.1038/s41593-023-01334-3. Epub 2023 Jun 1.

DOI:10.1038/s41593-023-01334-3
PMID:37264161
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10464935/
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.

摘要

脑血管失调是阿尔茨海默病（AD）的一个标志，但特定细胞类型中发生的变化尚未完全阐明。在这里，我们对 220 名 AD 患者和 208 名年龄匹配的对照者的六个大脑区域的 22,514 个人类脑血管细胞进行了单细胞转录组分析。我们注释了 22,514 个脑血管细胞，包括内皮细胞、周细胞、平滑肌细胞、周细胞成纤维细胞和室管膜细胞 11 种亚型。我们在 AD 中发现了 2,676 个差异表达的基因，包括周细胞中 PDGFRB 的下调，内皮细胞中 ABCB1 和 ATP10A 的下调，以及死后 AD 脑组织中 SLC6A1 的下调和 APOD、INSR 和 COL4A1 的上调。我们检测到血管、神经胶质和神经元共表达的基因模块，表明 AD 中神经血管单元的协调失调。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，我们表明 APOE4 基因型相关的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的亚群中，在 AD 相关基因中显著富集。

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