Sheffield Institute for Translational Neuroscience, University of Sheffield, 385 Glossop Road, S10 2HQ, Sheffield, UK.
Facultad de Medicina, Universidad de Málaga, 29010, Malaga, Spain.
Fluids Barriers CNS. 2024 Apr 11;21(1):34. doi: 10.1186/s12987-024-00528-6.
The blood-brain barrier (BBB) serves as a highly intricate and dynamic interface connecting the brain and the bloodstream, playing a vital role in maintaining brain homeostasis. BBB dysfunction has been associated with multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS); however, the role of the BBB in neurodegeneration is understudied. We developed an ALS patient-derived model of the BBB by using cells derived from 5 patient donors carrying C9ORF72 mutations. Brain microvascular endothelial-like cells (BMEC-like cells) derived from C9ORF72-ALS patients showed altered gene expression, compromised barrier integrity, and increased P-glycoprotein transporter activity. In addition, mitochondrial metabolic tests demonstrated that C9ORF72-ALS BMECs display a significant decrease in basal glycolysis accompanied by increased basal and ATP-linked respiration. Moreover, our study reveals that C9-ALS derived astrocytes can further affect BMECs function and affect the expression of the glucose transporter Glut-1. Finally, C9ORF72 patient-derived BMECs form leaky barriers through a cell-autonomous mechanism and have neurotoxic properties towards motor neurons.
血脑屏障（BBB）作为连接大脑和血液的高度复杂和动态界面，在维持脑内环境稳定方面发挥着重要作用。BBB 功能障碍与多种神经退行性疾病有关，包括肌萎缩侧索硬化症（ALS）；然而，BBB 在神经退行性变中的作用研究不足。我们通过使用来自 5 名携带 C9ORF72 突变的患者的细胞，开发了一种 ALS 患者来源的 BBB 模型。源自 C9ORF72-ALS 患者的脑微血管内皮样细胞（BMEC 样细胞）表现出改变的基因表达、受损的屏障完整性和增加的 P-糖蛋白转运体活性。此外，线粒体代谢测试表明，C9ORF72-ALS BMECs 显示基础糖酵解显著下降，同时基础和 ATP 连接呼吸增加。此外，我们的研究揭示了 C9-ALS 衍生的星形胶质细胞可以进一步影响 BMEC 功能，并影响葡萄糖转运蛋白 Glut-1 的表达。最后，C9ORF72 患者来源的 BMEC 通过自主细胞机制形成渗漏性屏障，并对运动神经元具有神经毒性。
