Exploring the role of Myelin Regulatory Factor in oligodendrocyte dysfunction in models of Alzheimer,s disease

Abstract

Amyloid ß oligomers (Aßo) induce oligodendrocyte and myelin dysfunctions in early stages of Alzheimer's disease, which contribute to cognitive deficits. Oligodendrocyte differentiation and myelination processes are tightly regulated by several transcriptional factor, among which Myelin Regulatory Factor (MYRF) is essential. However, MYRF¿s role in Alzheimer¿s disease remains poorly understood. In our study, we observed promoted oligodendrocyte differentiation and maturation in the corpus callosum and the dentate gyrus of both 3xTg-AD and Aßo-injected WT mice, in addition to brain region-specific oligodendrocyte cell death in the dentate gyrus of the 3xTg-AD mice. Additionally, Aßo exposure increased MYRF protein levels both in vivo and in vitro. We describe, for the first time, an Aßo-induced aberrant signaling pathway for MYRF degradation, with functional implications for oligodendrocytes and myelin in Alzheimer¿s disease models. Furthermore, we validate PKC inhibition as a potential pharmacological strategy to mitigate these disruptions in zebrafish and murine models.