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. Overall design: 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.