Department of Neurobiology, St. Joseph's Hospital and Medical Center and Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ, 85013, USA.
Gregory W. Fulton ALS Center, Barrow Neurological Institute, Phoenix, AZ, USA.
Acta Neuropathol Commun. 2020 Jun 26;8(1):92. doi: 10.1186/s40478-020-00968-9.
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.
脉络丛（CP）是一种位于脑室中的高度血管化结构，形成血脑屏障（BCSFB），将血液与脑脊液（CSF）分隔开。除了作为物理屏障的作用外，CP 还具有脑脊液分泌、营养物质向中枢神经系统（CNS）的转运以及循环免疫细胞进入 CNS 的门控点的功能。衰老和神经退行性变已被报道会影响 CP 的形态和功能，并增加蛋白质从血液漏入 CSF。肌萎缩侧索硬化症（ALS）是一种与上下运动神经元丧失以及 CSF 中蛋白质组学和代谢组学特征改变相关的神经退行性疾病。BCSFB 和 CP 在 ALS 中的作用尚不清楚。在这里，我们描述了对来自 ALS 和非神经疾病对照的人类死后组织中 BCSFB 和 CP 改变的转录组学和超微结构分析。ALS-CP 中 CP 上皮层和血管完整性的紧密连接成分广泛破坏。此外，我们检测到 ALS 血管周围周细胞丢失，伴随着血小板聚集标志物 vWF 和纤维蛋白原的激活，类似于血管损伤。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谱进行了全面分析，发现 ALS 中 M-CSF 和 V-CAM1 显著下调，以及 VEGF-A 蛋白上调。与对照组相比，这种表型伴随着 MERTK 阳性巨噬细胞浸润到 ALS-CP 的实质中。总之，我们证明了人类 ALS 中 BCSFB 的广泛结构和功能破坏，增加了我们对疾病病理学的理解，并确定了 ALS 治疗开发的潜在新靶点。
