小柯机器人

美国加州大学旧金山分校Tony Wyss-Coray研究小组揭示阿尔茨海默病风险的多种介导因素。相关论文于2022年2月14日在线发表于国际学术期刊《自然》。

研究人员开发了血管分离和细胞核提取测序（VINE-seq），通过来自9名阿尔茨海默病患者和8名无认知障碍者的25个海马和皮层样本的143,793个单核转录组，对人脑的主要血管和血管周围细胞类型进行了分析。研究人员确定了大脑区域的和物种富集的基因和途径。结果揭示了人类动静脉组织的分子原理，再现了一个渐进的内皮细胞和壁细胞的连续过程。研究人员发现了人类周细胞的两种亚型，以溶质运输和细胞外基质（ECM）组织为标志；并定义了血管周围与脑膜纤维细胞的特化。在阿尔茨海默病中，研究人员观察到维持ECM的周细胞选择性脆弱性和牵涉到血流失调的基因表达模式。

通过对脑细胞类型的扩大调查，研究人员发现在全基因组关联研究（GWAS）与阿尔茨海默病风险相关的前45个基因中，有30个基因在人脑血管中表达，并且通过免疫染色证实了这一点。血管GWAS基因映射到内皮细胞蛋白运输、适应性免疫和ECM途径。许多在小鼠中是小胶质细胞特异性的，这表明阿尔茨海默病风险的部分演化性转移。这项工作揭示了人类大脑血管的分子基础，这将为人们了解整个大脑健康、疾病和治疗提供信息。

据介绍，人脑血管在医学上具有重要意义，它的功能障碍导致残疾和死亡，它形成的专门结构（血脑屏障）阻碍了几乎所有脑部疾病的治疗。然而，到目前为止，人们还没有人类大脑血管的分子图谱。

附：英文原文

Title: A human brain vascular atlas reveals diverse mediators of Alzheimer’s risk

Author: Yang, Andrew C., Vest, Ryan T., Kern, Fabian, Lee, Davis P., Agam, Maayan, Maat, Christina A., Losada, Patricia M., Chen, Michelle B., Schaum, Nicholas, Khoury, Nathalie, Toland, Angus, Calcuttawala, Kruti, Shin, Heather, Plovics, Rbert, Shin, Andrew, Wang, Elizabeth Y., Luo, Jian, Gate, David, Schulz-Schaeffer, Walter J., Chu, Pauline, Siegenthaler, Julie A., McNerney, M. Windy, Keller, Andreas, Wyss-Coray, Tony

Issue&Volume: 2022-02-14

Abstract: The human brain vasculature is of great medical importance: its dysfunction causes disability and death1, and the specialized structure it forms—the blood–brain barrier—impedes the treatment of nearly all brain disorders2,3. Yet so far, we have no molecular map of the human brain vasculature. Here we develop vessel isolation and nuclei extraction for sequencing (VINE-seq) to profile the major vascular and perivascular cell types of the human brain through 143,793 single-nucleus transcriptomes from 25 hippocampus and cortex samples of 9 individuals with Alzheimer’s disease and 8 individuals with no cognitive impairment. We identify brain-region- and species-enriched genes and pathways. We reveal molecular principles of human arteriovenous organization, recapitulating a gradual endothelial and punctuated mural cell continuum. We discover two subtypes of human pericytes, marked by solute transport and extracellular matrix (ECM) organization; and define perivascular versus meningeal fibroblast specialization. In Alzheimer’s disease, we observe selective vulnerability of ECM-maintaining pericytes and gene expression patterns that implicate dysregulated blood flow. With an expanded survey of brain cell types, we find that 30 of the top 45 genes that have been linked to Alzheimer’s disease risk by genome-wide association studies (GWASs) are expressed in the human brain vasculature, and we confirm this by immunostaining. Vascular GWAS genes map to endothelial protein transport, adaptive immune and ECM pathways. Many are microglia-specific in mice, suggesting a partial evolutionary transfer of Alzheimer’s disease risk. Our work uncovers the molecular basis of the human brain vasculature, which will inform our understanding of overall brain health, disease and therapy.

DOI: 10.1038/s41586-021-04369-3

Source: https://www.nature.com/articles/s41586-021-04369-3

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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