ABCA7 deficiency compromises astrocytic lipid homeostasis and impairs neuronal support

Single-cell transcriptomic analysis of glia-enriched cortical organoids from isogenic control and ABCA7 knockout induced pluripotent stem cells (iPSCs) revealed cell type-specific effects of ABCA7 deficiency, including mitochondrial metabolism- and stress-associated signatures in astrocyte populations.

Lipidomic profiling revealed extensive remodeling in ABCA7-deficient iPSC-derived astrocytes, characterized by reduced cholesteryl esters, cholesterol, sphingomyelin, phosphatidylcholine, lysophosphatidylethanolamine and phosphatidylserine, and increased cardiolipin. These lipid alterations were accompanied by impaired cholesterol efflux and reduced lipid droplet formation. While mitochondrial respiration and glycolysis were heightened in ABCA7-deficient iPSC-derived astrocytes compared to controls, we found the increased mitochondrial reactive oxygen species and exacerbated ferroptosis-related phenotype.