Markoullis Kyriaki, Sargiannidou Irene, Schiza Natasa, Roncaroli Federico, Reynolds Richard, Kleopa Kleopas A
From the Neuroscience Laboratory (KM, IS, NS, KAK) and Neurology Clinics (KAK), The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; and Wolfson Neuroscience Laboratories, Division of Brain Sciences, Imperial College Faculty of Medicine, London, United Kingdom (FR, RR).
J Neuropathol Exp Neurol. 2014 Sep;73(9):865-79. doi: 10.1097/NEN.0000000000000106.
Gap junctions are essential for glial cell function and have been increasingly implicated in multiple sclerosis (MS). Because increasing cortical abnormalities correlate with disease progression and cognitive dysfunction, we examined the expression of oligodendrocytic connexin32 (Cx32) and Cx47 and their astrocytic partners Cx30 and Cx43 in cortical lesions and normal-appearing gray matter (NAGM) in MS patients. Postmortem brain tissue samples from 9 MS cases were compared with 10 controls using real-time polymerase chain reaction, immunoblot, and immunohistochemical analyses. Connexin32 and Cx47 gap junction formation in oligodendrocytes was reduced within lesions, whereas Cx32 loss also extended to NAGM. In contrast, astrocytic Cx30 expression was increased within cortical lesions, whereas Cx43 was elevated in both lesions and NAGM. Diffuse microglial activation and marked astrogliotic changes accompanied these connexin abnormalities. Increased expression of Cx43 correlated with inflammatory load (r = 0.828, p = 0.042), whereas Cx32 expression correlated with longer disease duration and, therefore, milder course (r = 0.825, p = 0.043). Thus, there is a loss of intramyelin and intercellular oligodendrocyte gap junctions in MS gray matter lesions and NAGM, whereas interastrocytic gap junctions are increased, reflecting astrogliosis. These changes correlate with inflammation and disease duration and suggest that disconnection of oligodendrocytes from reactive astrocytes may play a role in failed remyelination and disease progression.
缝隙连接对于胶质细胞功能至关重要，并且越来越多地与多发性硬化症（MS）相关。由于皮质异常增加与疾病进展和认知功能障碍相关，我们研究了少突胶质细胞连接蛋白32（Cx32）和Cx47及其星形胶质细胞伴侣Cx30和Cx43在MS患者皮质病变和外观正常灰质（NAGM）中的表达。使用实时聚合酶链反应、免疫印迹和免疫组织化学分析，将9例MS病例的死后脑组织样本与10例对照进行比较。少突胶质细胞中Cx32和Cx47缝隙连接的形成在病变内减少，而Cx32的缺失也扩展到NAGM。相反，星形胶质细胞Cx30在皮质病变内的表达增加，而Cx43在病变和NAGM中均升高。弥漫性小胶质细胞活化和明显的星形胶质细胞增生变化伴随着这些连接蛋白异常。Cx43表达增加与炎症负荷相关（r = 0.828，p = 0.042），而Cx32表达与更长的病程相关，因此病程较轻（r = 0.825，p = 0.043）。因此，MS灰质病变和NAGM中髓鞘内和少突胶质细胞间的缝隙连接丧失，而星形胶质细胞间的缝隙连接增加，反映了星形胶质细胞增生。这些变化与炎症和病程相关，提示少突胶质细胞与反应性星形胶质细胞的分离可能在髓鞘再生失败和疾病进展中起作用。
