Department of Veterinary Resources, The Weizmann Institute of Science, Rehovot, 761001, Israel.
Department of Neurobiology, The Weizmann Institute of Science, Rehovot, 761001, Israel.
Glia. 2018 May;66(5):1098-1117. doi: 10.1002/glia.23304. Epub 2018 Feb 9.
To elucidate mechanisms contributing to cortical pathology in multiple sclerosis (MS), we investigated neurovascular aberrations, in particular the association of astrocytes with cortical neurons and blood vessels, in mice induced with experimental autoimmune encephalomyelitis (EAE). Blood-brain barrier (BBB) dysfunction was evident by leakage of the tracer sodium fluorescein, along with reduced expression of claudin-5 by endothelial cells and desmin by pericytes. Immunohistological and ultrastructural analyses revealed detachment of the astroglial cell bodies from the blood vessels and loss of their connections with both the blood vessels and the neuronal synapses. Furthermore, examination of individual astrocytic processes at cortical layer IV, where well-defined neuronal columns (barrels) are linked to functional properties, revealed loss of astrocytic confinement to the functional neuronal boundaries. Thus, in contrast to the highly modulated patches of astrocyte processes in naïve mice overlapping the barrel cores, in EAE-mice process distribution was uniform ignoring the barrel boundaries. These aberrations are attributed to the surrounding inflammation, indicated by T-cells presence in the cortex as well as in the subcortical white matter and the meninges. Immunomodulatory treatment with glatiramer acetate partially abrogated the neurovascular damage. These combined findings indicate that under inflammatory conditions, activated perivascular astrocytes fail in neuro-hemodynamic coupling, resulting in obstructed cross-talk between the blood vessels and the neurons. We propose that loss of cortical astrocytic regulation and fine-tuning between the blood supply and the neuronal needs contributes to the neurological impairment and cognitive decline occurring in EAE/MS as well as to the disease progression.
为了阐明多发性硬化症（MS）皮质病变的发病机制，我们研究了神经血管异常，特别是小胶质细胞与皮质神经元和血管的关联，这些异常在实验性自身免疫性脑脊髓炎（EAE）诱导的小鼠中存在。血脑屏障（BBB）功能障碍表现为示踪剂荧光素钠的渗漏，同时内皮细胞的紧密连接蛋白 5 和周细胞的波形蛋白表达减少。免疫组织化学和超微结构分析显示，星形胶质细胞体与血管分离，并且它们与血管和神经元突触的连接丢失。此外，对皮质 IV 层的单个星形胶质细胞突起进行检查，在那里定义明确的神经元柱（桶）与功能特性相关，发现星形胶质细胞对功能性神经元边界的限制丧失。因此，与在未受刺激的小鼠中高度调节的、重叠桶核的星形胶质细胞突起斑块相比，在 EAE 小鼠中，突起分布是均匀的，忽略了桶边界。这些异常归因于周围炎症，这表明 T 细胞存在于皮质以及皮质下白质和脑膜中。用醋酸格拉替雷进行免疫调节治疗部分阻断了神经血管损伤。这些综合发现表明，在炎症条件下，激活的血管周细胞在神经血液耦联中失败，导致血管和神经元之间的通信受阻。我们提出，皮质星形胶质细胞调节的丧失以及血液供应和神经元需求之间的微调失调，导致 EAE/MS 中发生的神经功能障碍和认知能力下降，以及疾病进展。
