Aberrant activation of Wnt signaling in astrocytes mediates neuroinflammation- induced impairment of cholesterol homeostasis and myelinogenesis

However, the molecular mechanisms underlying these defects have remained enigmatic. In this study, we report that inflammation significantly activates Wnt signaling in astrocytes and induces astrocytic expression of SREBF2 protein, a key transcription factor for cholesterol synthesis, through direct binding of β-catenin/LEF1 complexes to the promoter region of Srebf2.

The astrocytic Wnt signaling activation simultaneously inhibits the expression of APOE, the critical apolipoprotein for cholesterol efflux, resulting in a reduced cholesterol supply from astrocytes to oligodendrocytes. The extracellular cholesterol supply is essential for the activation of myelin gene expression by MYRF transcription factor in oligodendrocytes. Moreover, the defective oligodendrocyte differentiation and myelin gene expression caused by astrocytic Wnt activation in transgenic mice can partially be rescued by chemical-enhanced Apoe expression.