Frontotemporal dementia (FTD) is the second most prevalent form of early-onset dementia, affecting predominantly frontal and temporal cerebral lobes. Heterozygous mutations in the progranulin gene (GRN) cause autosomal-dominant FTD (FTD-GRN), associated with TDP-43 inclusions, neuronal loss, axonal degeneration and gliosis, but FTD-GRN pathogenesis is largely unresolved. Here we report single-nucleus RNA sequencing of microglia, astrocytes and the neurovasculature from frontal, temporal and occipital cortical tissue from control and FTD-GRN brains. We show that fibroblast and mesenchymal cell numbers were enriched in FTD-GRN, and we identified disease-associated subtypes of astrocytes and endothelial cells. Expression of gene modules associated with blood–brain barrier (BBB) dysfunction was significantly enriched in FTD-GRN endothelial cells. The vasculature supportive function and capillary coverage by pericytes was reduced in FTD-GRN tissue, with increased and hypertrophic vascularization and an enrichment of perivascular T cells. Our results indicate a perturbed BBB and suggest that the neurovascular unit is severely affected in FTD-GRN.

额颞叶痴呆 (FTD) 是早发性痴呆的第二大流行形式，主要影响大脑额叶和颞叶。颗粒蛋白原基因 ( GRN )的杂合突变导致常染色体显性遗传性 FTD (FTD-GRN)，与 TDP-43 包涵体、神经元丢失、轴突变性和神经胶质增生相关，但 FTD-GRN 的发病机制在很大程度上尚未解决。在这里，我们报告了来自对照和 FTD-GRN 大脑的额叶、颞叶和枕叶皮质组织的小胶质细胞、星形胶质细胞和神经血管系统的单核 RNA 测序。我们发现成纤维细胞和间充质细胞数量在 FTD-GRN 中丰富，并且我们鉴定了星形胶质细胞和内皮细胞的疾病相关亚型。与血脑屏障 (BBB) 功能障碍相关的基因模块的表达在 FTD-GRN 内皮细胞中显着丰富。在 FTD-GRN 组织中，血管支持功能和周细胞的毛细血管覆盖减少，血管形成增加和肥厚，血管周围 T 细胞富集。