BackgroundBlood–brain barrier dysfunction is associated with many late-stage neurodegenerative diseases. An emerging question is whether the mutations associated with neurodegenerative diseases can independently lead to blood–brain barrier (BBB) dysfunction. Studies from patient-derived induced pluripotent stem cells suggest that mutations associated with neurodegenerative disease are non-cell autonomous, resulting in gain of toxic function in derived neurons and astrocytes. Here we assess whether selected mutations associated with neurodegenerative diseases can contribute to impairment of the blood–brain barrier.MethodsWe assessed barrier function of confluent monolayers of human brain microvascular endothelial cells (hBMECs) derived from induced pluripotent stem cells (iPSC) from three healthy individuals and eight individuals with neurodegenerative disease. We systematically assessed protein and gene expression of BBB biomarkers, transendothelial resistance (TEER), permeability of Lucifer yellow, permeability of d-glucose, permeability of rhodamine 123, the efflux ratio of rhodamine 123, and P-gp inhibition using Tariquidar for confluent monolayers of human brain microvascular endothelial cell (hBMECs).ResultsWe provide evidence supporting the hypothesis that mutations associated with neurodegenerative disease can independently cause BBB dysfunction. These functional changes are not catastrophic since barrier breakdown would result in BBB impairment during development. Synergistic interactions between non-cell autonomous cerebrovascular dysfunction and the effects of gain-of-toxic function in neurons (e.g. toxic oligomers) are likely to increase disease burden through a positive feedback mechanism.ConclusionsThese results suggest that the accumulation of defects in brain microvascular endothelial cells may ultimately lead to impairment of the BBB. Small changes in barrier function over time could lead to accumulated defects that result in positive feedback to unrelated central nervous system diseases.

中文翻译：

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与家族性神经退行性疾病相关的突变对 iPSC 模型中血脑屏障功能的作用

背景血脑屏障功能障碍与许多晚期神经退行性疾病有关。一个新出现的问题是与神经退行性疾病相关的突变是否可以独立导致血脑屏障 (BBB) 功能障碍。来自患者的诱导多能干细胞的研究表明，与神经退行性疾病相关的突变是非细胞自主的，导致衍生神经元和星形胶质细胞获得毒性功能。在这里，我们评估与神经退行性疾病相关的选定突变是否会导致血脑屏障受损。方法我们评估了来自三名健康个体和八名患有神经退行性疾病的诱导多能干细胞 (iPSC) 的人脑微血管内皮细胞 (hBMEC) 汇合单层的屏障功能。我们系统地评估了 BBB 生物标志物的蛋白质和基因表达、跨内皮抵抗 (TEER)、路西法黄的渗透性、d-葡萄糖的渗透性、罗丹明 123 的渗透性、罗丹明 123 的外排比以及使用 Tariquidar 对融合单层的 P-gp 抑制人脑微血管内皮细胞 (hBMECs)。结果我们提供证据支持与神经退行性疾病相关的突变可以独立导致 BBB 功能障碍的假设。这些功能变化不是灾难性的，因为屏障破坏会在发育过程中导致 BBB 损伤。非细胞自主脑血管功能障碍与神经元毒性功能获得效应（如毒性寡聚体）之间的协同相互作用可能通过正反馈机制增加疾病负担。结论这些结果表明脑微血管内皮缺陷的积累细胞可能最终导致 BBB 受损。随着时间的推移，屏障功能的微小变化可能会导致累积缺陷，从而导致对无关中枢神经系统疾病的积极反馈。毒性低聚物）可能通过正反馈机制增加疾病负担。结论这些结果表明，脑微血管内皮细胞缺陷的积累可能最终导致血脑屏障受损。随着时间的推移，屏障功能的微小变化可能会导致累积缺陷，从而导致对无关中枢神经系统疾病的积极反馈。毒性低聚物）可能通过正反馈机制增加疾病负担。结论这些结果表明，脑微血管内皮细胞缺陷的积累可能最终导致血脑屏障受损。随着时间的推移，屏障功能的微小变化可能会导致累积缺陷，从而导致对无关中枢神经系统疾病的积极反馈。