von Maydell Djuna, Wright Shannon E, Pao Ping-Chieh, Staab Colin, King Oisín, Spitaleri Andrea, Bonner Julia Maeve, Liu Liwang, Yu Chung Jong, Chiu Ching-Chi, Leible Daniel, Ni Scannail Aine, Li Mingpei, Boix Carles A, Mathys Hansruedi, Leclerc Guillaume, Menchaca Gloria Suella, Welch Gwyneth, Graziosi Agnese, Leary Noelle, Samaan George, Kellis Manolis, Tsai Li-Huei
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
Nature. 2025 Sep 10. doi: 10.1038/s41586-025-09520-y.
Loss-of-function variants in the lipid transporter ABCA7 substantially increase the risk of Alzheimer's disease, yet how they impact cellular states to drive disease remains unclear. Here, using single-nucleus RNA-sequencing analysis of human brain samples, we identified widespread gene expression changes across multiple neural cell types associated with rare ABCA7 loss-of-function variants. Excitatory neurons, which expressed the highest levels of ABCA7, showed disrupted lipid metabolism, mitochondrial function, DNA repair and synaptic signalling pathways. Similar transcriptional disruptions occurred in neurons carrying the common Alzheimer's-associated variant ABCA7 p.Ala1527Gly, predicted by molecular dynamics simulations to alter the ABCA7 structure. Induced pluripotent stem (iPS)-cell-derived neurons with ABCA7 loss-of-function variants recapitulated these transcriptional changes, displaying impaired mitochondrial function, increased oxidative stress and disrupted phosphatidylcholine metabolism. Supplementation with CDP-choline increased phosphatidylcholine synthesis, reversed these abnormalities and normalized amyloid-β secretion and neuronal hyperexcitability-key Alzheimer's features that are exacerbated by ABCA7 dysfunction. Our results implicate disrupted phosphatidylcholine metabolism in ABCA7-related Alzheimer's risk and highlight a possible therapeutic approach.
脂质转运蛋白ABCA7的功能丧失变异体显著增加了患阿尔茨海默病的风险，但它们如何影响细胞状态以引发疾病仍不清楚。在这里，我们通过对人类大脑样本进行单核RNA测序分析，确定了与罕见的ABCA7功能丧失变异体相关的多种神经细胞类型中广泛存在的基因表达变化。表达ABCA7水平最高的兴奋性神经元表现出脂质代谢、线粒体功能、DNA修复和突触信号通路的紊乱。携带常见的与阿尔茨海默病相关的变异体ABCA7 p.Ala1527Gly的神经元也出现了类似的转录紊乱，分子动力学模拟预测该变异体会改变ABCA7的结构。具有ABCA7功能丧失变异体的诱导多能干细胞（iPS）衍生神经元重现了这些转录变化，表现出线粒体功能受损、氧化应激增加和磷脂酰胆碱代谢紊乱。补充胞苷二磷酸胆碱可增加磷脂酰胆碱的合成，逆转这些异常，并使淀粉样β蛋白分泌和神经元过度兴奋正常化，而ABCA7功能障碍会加剧这些关键的阿尔茨海默病特征。我们的研究结果表明磷脂酰胆碱代谢紊乱与ABCA7相关的阿尔茨海默病风险有关，并突出了一种可能的治疗方法。
