Omar Omar M F, Kimble Amy L, Cheemala Ashok, Tyburski Jordan D, Pandey Swati, Wu Qian, Reese Bo, Jellison Evan R, Hao Bing, Li Yunfeng, Yan Riqiang, Murphy Patrick A
Center for Vascular Biology, University of Connecticut Medical School, Farmington, CT, USA.
Department of Pathology, University of Connecticut Medical School, Farmington, CT, USA.
Nat Neurosci. 2025 May;28(5):973-984. doi: 10.1038/s41593-025-01914-5. Epub 2025 Mar 14.
Endothelial cells (ECs) help maintain the blood-brain barrier but deteriorate in many neurodegenerative disorders. Here we show, using a specialized method to isolate EC and microglial nuclei from postmortem human cortex (92 donors, 50 male and 42 female, aged 20-98 years), that intranuclear cellular indexing of transcriptomes and epitopes enables simultaneous profiling of nuclear proteins and RNA transcripts at a single-nucleus resolution. We identify a disease-associated subset of capillary ECs in Alzheimer's disease, amyotrophic lateral sclerosis and frontotemporal degeneration. These capillaries exhibit reduced nuclear β-catenin and β-catenin-downstream genes, along with elevated TNF/NF-κB markers. Notably, these transcriptional changes correlate with the loss of nuclear TDP-43, an RNA-binding protein also depleted in neuronal nuclei. TDP-43 disruption in human and mouse ECs replicates these alterations, suggesting that TDP-43 deficiency in ECs is an important factor contributing to blood-brain barrier breakdown in neurodegenerative diseases.
内皮细胞（ECs）有助于维持血脑屏障，但在许多神经退行性疾病中会恶化。在这里，我们展示了一种使用专门方法从死后人类皮质（92名供体，50名男性和42名女性，年龄在20至98岁之间）中分离EC和小胶质细胞核的方法，即转录组和表位的核内细胞索引能够在单细胞核分辨率下同时分析核蛋白和RNA转录本。我们在阿尔茨海默病、肌萎缩侧索硬化症和额颞叶变性中鉴定出与疾病相关的毛细血管EC子集。这些毛细血管表现出核β-连环蛋白和β-连环蛋白下游基因减少，以及TNF/NF-κB标志物升高。值得注意的是，这些转录变化与核TDP-43的丧失相关，TDP-43是一种在神经元核中也会耗尽的RNA结合蛋白。在人和小鼠ECs中破坏TDP-43会重现这些改变，表明ECs中TDP-43的缺乏是导致神经退行性疾病血脑屏障破坏的一个重要因素。
