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. Furthermore, ABCA7-deficient iPSC-derived neurons showed compromised mitochondrial respiration and excess ROS generation, as well as enlarged mitochondrial morphology compared to the isogenic controls. ABCA7 deficiency also decreased spontaneous synaptic firing and network formation in iPSC-derived neurons, in which the effects were rescued by supplementation with phosphatidylglycerol or NAD⁺ precursor, nicotinamide mononucleotide. Importantly, effects of ABCA7 deficiency on mitochondria morphology and synapses were recapitulated in synaptosomes isolated from the brain of neuron-specific Abca7 knockout mice. Together, our results provide evidence that ABCA7 loss-of-function contributes to AD risk by modulating mitochondria lipid metabolism.

ABCA7 功能丧失变异与阿尔茨海默病 （AD） 风险增加有关。使用由 CRISPR/Cas9 生成的 ABCA7 敲除人类 iPSC 模型，我们研究了 ABCA7 缺陷对神经元代谢和功能的影响。脂质组学显示，在 ABCA7 缺陷型 iPSC 衍生的皮质类器官中，线粒体相关的磷脂（如磷脂酰甘油和心磷脂）减少。一致地，ABCA7 缺陷诱导的线粒体形态改变伴随着 ATP 合酶活性降低和类器官氧化损伤加剧。此外，与同基因对照相比，ABCA7 缺陷型 iPSC 衍生的神经元显示线粒体呼吸受损和 ROS 生成过多，以及线粒体形态扩大。ABCA7 缺乏还减少了 iPSC 衍生神经元中的自发突触放电和网络形成，其中通过补充磷脂酰甘油或 NAD ⁺ 前体烟酰胺单核苷酸来挽救这种影响。重要的是，ABCA7 缺陷对线粒体形态和突触的影响在从神经元特异性 Abca7 敲除小鼠大脑分离的突触体中进行了概括。总之，我们的结果提供了证据，证明 ABCA7 功能丧失通过调节线粒体脂质代谢导致 AD 风险。