麻省理工学院Li-Huei Tsai研究团队报道了ABCA7变异影响神经元中的磷脂酰胆碱和线粒体。这一研究成果发表在2025年9月10日出版的国际学术期刊《自然》上。

通过对人脑样本进行单核RNA测序分析，课题组发现了与罕见的ABCA7功能丧失变体相关的多种神经细胞类型中广泛存在的基因表达变化。ABCA7表达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破坏。类似的转录中断发生在携带常见阿尔茨海默病相关变异ABCA7 p.Ala1527Gly3的神经元中，通过分子动力学模拟预测会改变ABCA7的结构。具有ABCA7功能丧失变体的诱导多能干细胞（iPS）来源的神经元再现了这些转录变化，表现出线粒体功能受损、氧化应激增加和磷脂酰胆碱代谢中断。补充CDP-胆碱可增加磷脂酰胆碱合成，逆转这些异常，并使淀粉样蛋白-β分泌和神经元高兴奋性正常化——这是ABCA7功能障碍加剧的关键阿尔茨海默病特征。他们的研究结果表明，磷脂酰胆碱代谢紊乱与ABCA7相关的阿尔茨海默病风险有关，并强调了一种可能的治疗方法。

据介绍，脂质转运体ABCA7的功能缺失变异大大增加了阿尔茨海默病的风险，但它们如何影响细胞状态以驱动疾病仍不清楚。

附：英文原文

Title: ABCA7 variants impact phosphatidylcholine and mitochondria in neurons

Author: von Maydell, Djuna, Wright, Shannon E., Pao, Ping-Chieh, Staab, Colin, King, Oisn, 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

Issue&Volume: 2025-09-10

Abstract: Loss-of-function variants in the lipid transporter ABCA7 substantially increase the risk of Alzheimer’s disease1,2, 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.Ala1527Gly3, 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.

DOI: 10.1038/s41586-025-09520-y

Source: https://www.nature.com/articles/s41586-025-09520-y