AD文献阅读第4期：Nature—APOE4通过诱导少突胶质细胞胆固醇代谢障碍进而驱动髓鞘损害

中文摘要

APOE4是阿尔茨海默病最强的遗传风险因子。然而，APOE4对人类大脑的影响尚未被完全了解，这限制了为携带APOE4和其他阿尔茨海默病风险因素的个体开发靶向治疗药物的机会。在此，为了更全面地了解APOE4对于人脑的影响，研究人员对APOE4携带者与非携带者的死后人脑组织进行了单细胞转录组学分析，发现APOE4与人类大脑所有细胞类型的广泛基因表达变化有关。与APOE的生物学功能一致，APOE4显著改变了与胆固醇稳态和转运相关的信号通路。通过对死后人脑、诱导的多能干细胞衍生细胞和靶向替代小鼠的组织学和脂质组学分析，他们证实了这些发现，胆固醇异常沉积在维持绝缘和促进神经元电活动的少突胶质细胞髓鞘形成细胞中。他们发现胆固醇在APOE4大脑中定位的改变与髓鞘形成减少相一致。药理学促进胆固醇转运可增加APOE4小鼠的轴突髓鞘形成并改善学习和记忆。因此，科学家提供了一个单细胞图谱，描述APOE4对衰老人脑的转录调控作用，并建立了APOE4、胆固醇、髓鞘形成和记忆之间的功能联系，为阿尔茨海默病提供了治疗策略。

英文摘要

APOE4 is the strongest genetic risk factor for Alzheimer's disease1-3. However, the effects of APOE4 on the human brain are not fully understood, limiting opportunities to develop targeted therapeutics for individuals carrying APOE4 and other risk factors for Alzheimer's disease4-8. Here, to gain more comprehensive insights into the impact of APOE4 on the human brain, we performed single-cell transcriptomics profiling of post-mortem human brains from APOE4 carriers compared with non-carriers. This revealed that APOE4 is associated with widespread gene expression changes across all cell types of the human brain. Consistent with the biological function of APOE2-6, APOE4 significantly altered signalling pathways associated with cholesterol homeostasis and transport. Confirming these findings with histological and lipidomic analysis of the post-mortem human brain, induced pluripotent stem-cell-derived cells and targeted-replacement mice, we show that cholesterol is aberrantly deposited in oligodendrocytes-myelinating cells that are responsible for insulating and promoting the electrical activity of neurons. We show that altered cholesterol localization in the APOE4 brain coincides with reduced myelination. Pharmacologically facilitating cholesterol transport increases axonal myelination and improves learning and memory in APOE4 mice. We provide a single-cell atlas describing the transcriptional effects of APOE4 on the aging human brain and establish a functional link between APOE4, cholesterol, myelination and memory, offering therapeutic opportunities for Alzheimer's disease.

参考文献：APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes.Nature. 2022 Nov 16. doi: 10.1038/s41586-022-05439-w.

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