PKC-dependent MYRF dysregulation links Aß pathology to oligodendrocyte, myelin and cognitive alterations in Alzheimer's disease
Alzheimer's disease (AD) is characterized not only by neuronal loss and synaptic dysfunction but also by emerging evidence of oligodendrocyte and myelin pathology. Amyloid-ß (Aß), a hallmark of AD, disrupts oligodendrocyte homeostasis through mechanisms that remain poorly understood. Here, we investigated the role of the myelin regulatory factor (MYRF), a transcription factor essential for oligodendrocyte maturation, in AD-related glial dysfunction. Using the 3xTg-AD mouse model, we observed aberrantly induced maturation dynamics and reduced oligodendrocyte lineage cell density at 12 months in the dentate gyrus, accompanied by increased MYRF expression. Interestingly, sustained MYRF overexpression was found to be toxic for oligodendrocytes in vitro. Moreover, in vitro and in vivo experiments further demonstrated that Aß exposure elevates MYRF protein levels and enhances its transcriptional activity, pointing to post-translational regulation. Mechanistically, Aß impaired GSK3-dependent phosphorylation and Fbxw7-mediated ubiquitination of MYRF, prolonging N-MYRF stability, an effect prevented by PKC inhibition in vitro. Intracerebroventricular infusion of PKC inhibitor Gö6983 normalized MYRF levels, restored oligodendrocyte populations and myelin integrity, and improved hippocampal-dependent spatial learning in 3xTg-AD mice, with locomotor activity and anxiety-like behavior remaining unaffected. Together, these findings identify MYRF dysregulation as a mechanistic link between Aß/PKC signaling and oligodendrocyte pathology, and highlight PKC inhibition as a potential strategy to restore oligodendroglial function and cognition in AD.