Genome-wide CRISPR screen reveals that Wnt signaling regulates lipid accumulation in APOE4 oligodendrocytes.

Inhibition of GSK3B reduces lipid droplet accumulation and improves myelination in APOE4 oligodendrocytes and mouse models, highlighting GSK3B as a therapeutic target.

• Why it matters: Understanding how APOE4 influences lipid metabolism and myelination in oligodendrocytes is crucial for developing targeted treatments for Alzheimer's disease risk associated with APOE4.
• What they did: A genome-wide CRISPR screen and ATAC sequencing in human iPSC-derived oligodendrocytes identified decreased Wnt signaling and overactive GSK3B as key regulators; pharmacological and genetic GSK3B inhibition was tested in cell cultures and APOE4;PS19 tau transgenic mice.
• The result: GSK3B inhibition reduced lipid droplets and enhanced myelination in APOE4 oligodendrocytes and mouse models, suggesting GSK3B as a promising therapeutic target for APOE4-related Alzheimer's disease.