The choroid plexus (CP) is a highly vascularized structure located in the ventricles that forms the blood-CSF barrier (BCSFB) and separates the blood from the cerebrospinal fluid (CSF). In addition to its role as a physical barrier, the CP functions in CSF secretion, transport of nutrients into the central nervous system (CNS) and a gated point of entry of circulating immune cells into the CNS. Aging and neurodegeneration have been reported to affect CP morphology and function and increase protein leakage from blood to the CSF. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with both upper and lower motor neuron loss, as well as altered proteomic and metabolomic signatures in the CSF. The role of the BCSFB and the CP in ALS is unknown. Here we describe a transcriptomic and ultrastructural analysis of BCSFB and CP alterations in human postmortem tissues from ALS and non-neurologic disease controls. ALS-CP exhibited widespread disruptions in tight junctional components of the CP epithelial layer and vascular integrity. In addition, we detected loss of pericytes around ALS blood vessels, accompanied by activation of platelet aggregation markers vWF and Fibrinogen, reminiscent of vascular injury. To investigate the immune component of ALS-CP, we conducted a comprehensive analysis of cytokines and chemokine panels in CP lysates and found a significant down-regulation of M-CSF and V-CAM1 in ALS, as well as up-regulation of VEGF-A protein. This phenotype was accompanied by an infiltration of MERTK positive macrophages into the parenchyma of the ALS-CP when compared to controls. Taken together, we demonstrate widespread structural and functional disruptions of the BCSFB in human ALS increasing our understanding of the disease pathology and identifying potential new targets for ALS therapeutic development.

中文翻译：

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肌萎缩性侧索硬化中脉络丛血CSF屏障的整体改变。

脉络丛（CP）是位于脑室的高度血管化结构，形成血CSF屏障（BCSFB）并将血液与脑脊液（CSF）分离。CP除了具有物理屏障的功能外，还具有CSF分泌，营养物质向中枢神经系统（CNS）的运输以及循环免疫细胞进入CNS的门控点的功能。据报道，衰老和神经退行性变会影响CP的形态和功能，并增加蛋白质从血液向CSF的泄漏。肌萎缩性侧索硬化症（ALS）是一种神经退行性疾病，与上，下运动神经元丢失以及CSF中蛋白质组学和代谢组学特征改变有关。BCSFB和CP在ALS中的作用尚不清楚。在这里，我们描述了从ALS和非神经系统疾病控制的人类死后组织中BCSFB和CP改变的转录组学和超微结构分析。ALS-CP在CP上皮层的紧密连接部分和血管完整性方面表现出广泛的破坏。此外，我们检测到了ALS血管周围周细胞的丢失，并伴有血小板聚集标志物vWF和纤维蛋白原的激活，令人联想到血管损伤。为了研究ALS-CP的免疫成分，我们对CP裂解物中的细胞因子和趋化因子进行了全面分析，发现ALS中M-CSF和V-CAM1显着下调，以及VEGF-CP上调一种蛋白质。与对照相比，该表型伴有MERTK阳性巨噬细胞浸润到ALS-CP的实质中。