Modeling Alpha-Synuclein Pathology in a Human Brain-Chip to Assess Blood-Brain Barrier Disruption

Experimental Parkinson's disease (PD) models, such as animal models or conventional cell culture systems, have advanced our understanding of the role of αSyn and its aggregated forms in the development of the disease and the induction of neuronal toxicity. However, these models have not been able to uncover the dynamics of the specific interactions between the brain parenchymal cells and the BBB in normal or pathological states. To address this need, we exposed the human Brain-Chip to αSyn fibrils that led to a progressive accumulation of phosphorylated αSyn and the associated induction of specific aspects of αSyn toxicity, such as mitochondrial dysfunction and oxidative stress. We also found that exposure of Brain-Chip to αSyn fibrils results in microglial activation, astrogliosis, and a time-dependent neuronal loss, as described in PD patients. Finally, our results show tight junctions' derangement and progressively compromised BBB permeability in response to αSyn fibrils. This is in line with previous studies showing deregulation of claudin as a key determinant of the BBB integrity and paracellular permeability. Interestingly, control over the amount of αSyn accumulation by treatment with the autophagy inducer trehalose rescued the compromised BBB permeability and the derangement of the tight junctions, suggesting a prospective therapeutic approach for treating compromised BBB implicated in PD. The purpose of this database is to provide the microscope images that have led to the conclusions shown in this report.实验性帕金森病（Parkinson's disease, PD）模型，如动物模型或传统细胞培养体系，已推动我们对α突触核蛋白（αSyn）及其聚集形式在疾病发生发展与神经元毒性诱导过程中所发挥作用的理解。然而，此类模型尚无法揭示正常或病理状态下脑实质细胞与血脑屏障（blood-brain barrier, BBB）之间特异性相互作用的动态变化。 为填补这一研究空白，我们将人类脑芯片（Human Brain-Chip）暴露于αSyn原纤维中，结果观察到磷酸化αSyn进行性蓄积，并伴随αSyn毒性相关病理特征的出现，例如线粒体功能障碍与氧化应激。我们还发现，脑芯片经αSyn原纤维刺激后，可引发小胶质细胞激活、星形胶质细胞增生，以及如帕金森病患者中所见的时间依赖性神经元丢失。最终，我们的研究结果显示，经αSyn原纤维刺激后，紧密连接（tight junctions）出现紊乱，血脑屏障通透性呈进行性受损。这与既往研究结论一致，后者显示紧密连接蛋白（claudin）的表达失调是维持血脑屏障完整性与细胞旁通透性的关键决定因素。值得注意的是，通过使用自噬诱导剂（autophagy inducer）海藻糖（trehalose）调控αSyn的蓄积量，可挽救受损的血脑屏障通透性与紧密连接紊乱，这提示了一种可用于治疗帕金森病相关血脑屏障受损的潜在治疗策略。 本数据库的目的在于提供支撑本报告中各项结论的显微镜成像数据。