ABCA7 deficiency causes neuronal dysregulation by altering mitochondrial lipid metabolism

ABCA7 loss-of-function variants are associated with increased risk of Alzheimer’s disease (AD). Using ABCA7 knockout human iPSC models generated with CRISPR/Cas9, we investigated the impacts of ABCA7 deficiency on neuronal metabolism and function. Lipidomics revealed that mitochondria-related phospholipids, such as phosphatidylglycerol and cardiolipin were reduced in the ABCA7-deficient iPSC-derived cortical organoids. Consistently, ABCA7 deficiency induced alterations of mitochondrial morphology accompanied by reduced ATP synthase activity and exacerbated oxidative damage in the organoids. In order to investigate the ABCA7 loss of function in human cells, we generated isogenic ABCA7 knockout iPSC lines by using CRISPR/Cas9. The iPSCs were differentiated into cortical organoids and analyzed 60 days after the differentiation.