Oligodendrocyte and myelin dysfunctions are early events in Alzheimer’s disease (AD). Oligodendrocyte maturation and myelination are strictly controlled by transcription factors (TF) such as myelin regulatory factor (MYRF). Self‑cleaved N-MYRF fragment translocates from the ER into the nucleus, where it induces expression of myelin genes. Subsequently, this fragment is phosphorylated by GSK3 and degraded via ubiquitin-proteasome system. Despite the relevance of MYRF in oligodendrocytes and myelin, little is known about its role in AD. Here, we report increased MYRF levels in amyloid b oligomer (Ab_o)-treated oligodendrocytes in vitro. By luciferase assays performed in primary oligodendrocytes, we revealed that Aβ_o promote myelin gene expression, an effect that was reverted by Myrf siRNA. Intracerebral injections of Ab_o also increased MYRF levels and promoted oligodendrocyte differentiation and maturation in WT mice. Similarly, 3xTg-AD mice also show more differentiated oligodendrocytes in contrast to WT mice. Mechanistically, we found a slower degradation of N‑MYRF by a cycloheximide chase assay and reduced levels of phosphorylated N-MYRF in Aβ_o-treated oligodendrocytes in vitro. Furthermore, the ubiquitination state of MYRF was also changed in presence of Aβ. Altogether, these results suggest that enhanced oligodendrocyte maturation in AD may be mediated by altered MYRF degradation.

https://www.achucarro.org/laboratory/neurobiology/