Researchers linked APOE4-associated lipid accumulation in human oligodendrocytes to altered Wnt/GSK3B signaling. A GSK3B inhibitor reduced lipid droplets in cell cultures and increased myelination in brain organoids; the findings remain preclinical.
An MIT-led team used a genome-wide CRISPR screen in oligodendrocytes derived from human induced pluripotent stem cells (iPSCs) carrying APOE4, an Alzheimer’s disease risk variant.
According to MIT’s report, the researchers also compared chromatin accessibility in cultured cells and postmortem human brain samples. Together, the analyses implicated reduced Wnt signaling and overactivity of the kinase glycogen synthase kinase-3 beta (GSK3B) in lipid-droplet accumulation in these myelin-producing cells.
In APOE4 oligodendrocyte cultures, the GSK3B inhibitor CHIR99021 reduced lipid droplets. In three-dimensional organoid cultures combining APOE4 oligodendrocytes with neurons, GSK3B inhibition increased myelination and axon growth, according to MIT’s report.
The study also tested GSK3B inhibition in APOE4;PS19 tau-model mice. In the hippocampus, treatment reduced lipid droplets and increased myelination compared with untreated controls.
A Westlake University team trained an image-analysis framework with fluorescence-derived labels, then used bright-field images to estimate viability and death patterns. A 24-compound A2780 screen revealed responses that bulk ATP measurements alone did not distinguish.
A Research Square preprint quantified uptake of 13 drugs in human-cell blood–brain barrier organoids. For measurable drugs, organoid uptake ratios correlated with published mammalian brain-to-plasma data, although the reference data and organoids themselves varied.
