APOE4 is the strongest genetic risk factor for late‑onset Alzheimer’s disease. A new study shows that it impairs neuronal myelination by suppressing Wnt signaling in oligodendrocytes, causing lipid‑droplet accumulation and defective myelin formation. Using a genome‑wide CRISPR knockout screen in human APOE4‑carrying oligodendrocytes, the authors found that loss of genes that promote Wnt activity leads to droplet buildup, while loss of Wnt repressors produces the same phenotype, highlighting Wnt dysregulation as a central mechanism.
Parallel ATAC‑seq analysis of APOE4 versus neutral APOE3 samples revealed reduced chromatin accessibility of Wnt‑related genes in APOE4 cells, confirming transcriptional repression. Molecular profiling showed decreased β‑catenin (a Wnt activator) and increased GSK3β (a Wnt inhibitor) in APOE4 oligodendrocytes.
Pharmacological manipulation of GSK3β demonstrated causality: the activator Dif3 increased lipid droplets in APOE3 cultures, whereas the inhibitor CHIR99021 reduced droplets in APOE4 cells, restored myelination, and promoted axon growth in organoid co‑cultures. In APOE4‑expressing mice modeling Alzheimer’s tau pathology, CHIR99021 treatment lowered hippocampal lipid droplets and enhanced myelin density.
These findings elucidate how APOE4‑driven Wnt suppression alters lipid metabolism in oligodendrocytes and propose GSK3β inhibition as a proof‑of‑concept therapeutic strategy. Future work will probe the link between GSK3β activity and tau phosphorylation, as well as additional metabolic regulators uncovered by the CRISPR screen.
Review