Neurobiology Department, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus.
Medical School, University of Nicosia, Nicosia 2414, Cyprus.
Int J Mol Sci. 2022 Dec 9;23(24):15597. doi: 10.3390/ijms232415597.
Gap junctions (GJs) are specialized transmembrane channels assembled by two hemi-channels of six connexin (Cx) proteins that facilitate neuroglial crosstalk in the central nervous system (CNS). Previous studies confirmed the crucial role of glial GJs in neurodegenerative disorders with dementia or motor dysfunction including Alzheimer's disease (AD). The aim of this study was to examine the alterations in astrocyte and related oligodendrocyte GJs in association with Aβ plaques in the spinal cord of the 5xFAD mouse model of AD. Our analysis revealed abundant Aβ plaque deposition, activated microglia, and astrogliosis in 12-month-old (12M) 5xFAD mice, with significant impairment of motor performance starting from 3-months (3M) of age. Additionally, 12M 5xFAD mice displayed increased immunoreactivity of astroglial Cx43 and Cx30 surrounding Aβ plaques and higher protein levels, indicating upregulated astrocyte-to-astrocyte GJ connectivity. In addition, they demonstrated increased numbers of mature CC1-positive and precursor oligodendrocytes (OPCs) with higher immunoreactivity of Cx47-positive GJs in individual cells. Moreover, total Cx47 protein levels were significantly elevated in 12M 5xFAD, reflecting increased oligodendrocyte-to-oligodendrocyte Cx47-Cx47 GJ connectivity. In contrast, we observed a marked reduction in Cx32 protein levels in 12M 5xFAD spinal cords compared with controls, while qRT-PCR analysis revealed a significant upregulation in mRNA levels. Finally, myelin deficits were found focally in the areas occupied by Aβ plaques, whereas axons themselves remained preserved. Overall, our data provide novel insights into the altered glial GJ expression in the spinal cord of the 5xFAD model of AD and the implicated role of GJ pathology in neurodegeneration. Further investigation to understand the functional consequences of these extensive alterations in oligodendrocyte-astrocyte (O/A) GJ connectivity is warranted.
缝隙连接 (GJ) 是由六个连接蛋白 (Cx) 组成的半通道组成的特殊跨膜通道，促进中枢神经系统 (CNS) 中的神经胶质细胞通讯。先前的研究证实了胶质 GJ 在痴呆或运动功能障碍相关神经退行性疾病中的关键作用，包括阿尔茨海默病 (AD)。本研究旨在检查 AD 5xFAD 小鼠模型脊髓中与 Aβ 斑块相关的星形胶质细胞和相关少突胶质细胞 GJ 的变化。我们的分析显示，12 个月大 (12M) 的 5xFAD 小鼠有大量 Aβ 斑块沉积、激活的小胶质细胞和星形胶质细胞增生，从 3 个月 (3M) 开始运动功能显著受损。此外，12M 5xFAD 小鼠显示 Aβ 斑块周围星形胶质细胞 Cx43 和 Cx30 的免疫反应性增加，蛋白水平升高，表明星形胶质细胞-星形胶质细胞 GJ 连接增加。此外，它们表现出更多的成熟 CC1 阳性和前体少突胶质细胞 (OPC)，细胞内 Cx47 阳性 GJ 的免疫反应性增加。此外，总 Cx47 蛋白水平在 12M 5xFAD 中显著升高，反映出少突胶质细胞-少突胶质细胞 Cx47-Cx47 GJ 连接增加。相比之下，我们观察到与对照组相比，12M 5xFAD 脊髓中的 Cx32 蛋白水平明显降低，而 qRT-PCR 分析显示其 mRNA 水平显著上调。最后，发现 Aβ 斑块占据的区域内出现局灶性髓鞘缺失，而轴突本身保持完好。总的来说，我们的数据提供了关于 AD 的 5xFAD 模型脊髓中改变的胶质 GJ 表达以及 GJ 病理学在神经退行性变中的潜在作用的新见解。进一步研究以了解少突胶质细胞-星形胶质细胞 (O/A) GJ 连接的这些广泛改变的功能后果是必要的。
