Ktena Niki, Spyridakos Dimitrios, Georgilis Alexandros, Kalafatakis Ilias, Thomoglou Efstathia, Kolaxi Angeliki, Nikoletopoulou Vassiliki, Savvaki Maria, Karagogeos Domna
School of Medicine, University of Crete, Heraklion, Greece.
Institute of Molecular Biology & Biotechnology-FORTH, Heraklion, Greece.
Glia. 2025 Jul;73(7):1383-1397. doi: 10.1002/glia.70012. Epub 2025 Mar 19.
The aging central nervous system (CNS) is often marked by myelin degeneration, yet the underlying mechanisms remain elusive. This study delves into the previously unexplored role of autophagy in maintaining CNS myelin during aging. We generated the transgenic mouse line plpCre ; atg5 , enabling selective deletion of the core autophagic component Atg5 in oligodendrocytes (OLs) following tamoxifen administration in adulthood, while analysis was conducted on aged mice. Our findings reveal that oligodendroglial autophagy inactivation leads to significant alterations in myelin protein levels. Moreover, the ultrastructural analysis revealed pronounced myelin deficits and increased degeneration of axons, accompanied by apoptosis, as confirmed by immunohistochemistry. Behaviorally, aged knockout (cKO) mice exhibited marked deficits in learning and memory tasks, indicative of cognitive impairment. Additionally, we observed increased activation of microglia, suggesting an inflammatory response linked to the absence of autophagic activity in OLs. These results underscore the critical role of autophagy in OLs for the preservation of CNS myelin and axonal integrity during aging. Our study highlights autophagy as a vital mechanism for neural maintenance, offering potential therapeutic avenues for combating age-related neurodegenerative diseases.
衰老的中枢神经系统（CNS）常以髓鞘变性为特征，但其潜在机制仍不清楚。本研究深入探讨了自噬在衰老过程中维持中枢神经系统髓鞘方面此前未被探索的作用。我们构建了转基因小鼠品系plpCre ; atg5 ，在成年期给予他莫昔芬后，可使少突胶质细胞（OLs）中核心自噬成分Atg5被选择性敲除，同时对老年小鼠进行分析。我们的研究结果表明，少突胶质细胞自噬失活会导致髓鞘蛋白水平发生显著变化。此外，超微结构分析显示髓鞘明显缺失，轴突变性增加，并伴有免疫组化证实的细胞凋亡。行为学上，老年基因敲除（cKO）小鼠在学习和记忆任务中表现出明显缺陷，表明存在认知障碍。此外，我们观察到小胶质细胞的激活增加，提示与少突胶质细胞中自噬活性缺失相关的炎症反应。这些结果强调了自噬在少突胶质细胞中对于衰老过程中维持中枢神经系统髓鞘和轴突完整性的关键作用。我们的研究突出了自噬作为神经维持的重要机制，为对抗与年龄相关的神经退行性疾病提供了潜在的治疗途径。
