Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683 Nicosia, Cyprus.
Acta Neuropathol. 2012 Jun;123(6):873-86. doi: 10.1007/s00401-012-0978-4. Epub 2012 Apr 7.
Oligodendrocyte gap junctions (GJs) are vital for central nervous system myelination, but their involvement in multiple sclerosis (MS) pathology remains unknown. The aim of this study was to examine alterations of oligodendrocyte and related astrocyte GJs in MS lesions and normal-appearing white matter (NAWM). Post-mortem brain samples from 9 MS and 11 age-matched non-MS control patients were studied. Tissue sections that included both chronic active and inactive lesions were characterized neuropathologically with Luxol Fast Blue staining and immunostaining for myelin oligodendrocyte glycoprotein (MOG) and the microglial marker Iba1. We analyzed the expression of Cx32 and Cx47 in oligodendrocytes and of Cx43, the major astrocytic partner in oligodendrocyte-astrocyte (O/A) GJs by quantitative immunoblot and real-time PCR. Formation of GJ plaques was quantified by immunohistochemistry. Compared to control brains, both Cx32 and Cx47 GJ plaques and protein levels were reduced in and around MS lesions, while Cx43 was increased as part of astrogliosis. In the NAWM, Cx32 was significantly reduced along myelinated fibers whereas Cx47 showed increased expression mainly in oligodendrocyte precursor cells (OPCs). However, OPCs showed only limited connectivity to astrocytes. Cx43 showed modestly increased levels in MS NAWM compared to controls, while GJ plaque counts were unchanged. Our findings indicate that oligodendrocyte GJs are affected not only in chronic MS lesions but also in NAWM, where disruption of Cx32 GJs in myelinated fibers may impair myelin structure and function. Moreover, limited O/A GJ connectivity of recruited OPCs in the setting of persistent inflammation and astrogliosis may prevent differentiation and remyelination.
少突胶质细胞缝隙连接（GJ）对中枢神经系统髓鞘形成至关重要，但它们在多发性硬化症（MS）病理学中的作用仍不清楚。本研究旨在研究 MS 病变和正常表现白质（NAWM）中少突胶质细胞和相关星形胶质细胞 GJ 的变化。研究了 9 例 MS 和 11 例年龄匹配的非 MS 对照患者的死后脑样本。使用卢索快速蓝染色和髓鞘少突胶质细胞糖蛋白（MOG）和小胶质细胞标志物 Iba1 的免疫染色对包括慢性活动性和非活动性病变的组织切片进行神经病理学特征描述。我们通过定量免疫印迹和实时 PCR 分析了少突胶质细胞中 Cx32 和 Cx47 的表达以及少突胶质细胞-星形胶质细胞（O/A）GJ 的主要星形胶质细胞伴侣 Cx43 的表达。通过免疫组织化学量化 GJ 斑块的形成。与对照脑相比，MS 病变内和周围的 Cx32 和 Cx47 GJ 斑块和蛋白水平均降低，而 Cx43 则作为星形胶质细胞增生的一部分增加。在 NAWM 中，Cx32 沿有髓纤维明显减少，而 Cx47 主要在少突胶质细胞前体细胞（OPC）中表达增加。然而，OPC 与星形胶质细胞的连接有限。与对照组相比，MS NAWM 中的 Cx43 水平略有增加，而 GJ 斑块计数不变。我们的研究结果表明，少突胶质细胞 GJ 不仅在慢性 MS 病变中受到影响，而且在 NAWM 中也受到影响，在髓鞘纤维中 Cx32 GJ 的破坏可能会损害髓鞘的结构和功能。此外，在持续的炎症和星形胶质细胞增生的情况下，募集的 OPC 之间有限的 O/A GJ 连接可能会阻止分化和髓鞘形成。
