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 ERT2 ; atg5 f/f , 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.
Keywords: CNS; aging; autophagy; myelin; neurodegeneration.
© 2025 The Author(s). GLIA published by Wiley Periodicals LLC.