美国西奈山伊坎医学院Alison M. Goate和美国波士顿大学医学院Julia TCW共同合作近期取得重要工作进展，他们研究发现星形胶质细胞和小胶质细胞中的胆固醇和基质体途径失调。该项研究成果2022年6月23日在线发表于《细胞》杂志上。
在这里，研究人员调查了APOE4对来自群体和同基因人类诱导多能干细胞、死后大脑和APOE靶向替代小鼠的脑细胞类型的影响。群体和同基因模型表明APOE4局部单倍型而不是单个风险等位基因会导致风险。全基因转录组分析揭示了星形胶质细胞和小胶质细胞中人类特异性、APOE4驱动的脂质代谢失调。尽管由于溶酶体胆固醇在星形细胞中被封存导致细胞内胆固醇升高，但APOE4增强了新的胆固醇合成。
此外，基质体失调与与神经元共培养的星形胶质细胞的趋化性、神经胶质激活和脂质生物合成上调有关，这概括了人脑中星形胶质细胞基质体信号的改变。因此，APOE4启动了胶质细胞和非细胞自主失调，可能有助于增加AD风险。
据介绍，载脂蛋白E ε4 (APOE4)是阿尔茨海默病(AD)的最强遗传风险因素，但它对人类脑细胞的功能影响尚不清楚。
附：英文原文
Title: Cholesterol and matrisome pathways dysregulated in astrocytes and microglia
Author: Julia TCW, Lu Qian, Nina H. Pipalia, Michael J. Chao, Shuang A. Liang, Yang Shi, Bharat R. Jain, Sarah E. Bertelsen, Manav Kapoor, Edoardo Marcora, Elizabeth Sikora, Elizabeth J. Andrews, Alessandra C. Martini, Celeste M. Karch, Elizabeth Head, David M. Holtzman, Bin Zhang, Minghui Wang, Frederick R. Maxfield, Wayne W. Poon, Alison M. Goate
Issue&Volume: 2022/06/23
Abstract: The impact of apolipoprotein E ε4 (APOE4), the strongest genetic risk factor for Alzheimer’s disease (AD), on human braincellular function remains unclear. Here, we investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotentstem cells, post-mortem brain, and APOE targeted replacement mice. Population and isogenic models demonstrate that APOE4 local haplotype, rather than a single risk allele, contributes to risk. Global transcriptomicanalyses reveal human-specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia. APOE4 enhances de novo cholesterol synthesis despite elevated intracellular cholesterol due to lysosomalcholesterol sequestration in astrocytes. Further, matrisome dysregulation is associatedwith upregulated chemotaxis, glial activation, and lipid biosynthesis in astrocytesco-cultured with neurons, which recapitulates altered astrocyte matrisome signalingin human brain. Thus, APOE4 initiates glia-specific cell and non-cell autonomous dysregulation that may contributeto increased AD risk.
DOI: 10.1016/j.cell.2022.05.017
Source: https://www.cell.com/cell/fulltext/S0092-8674(22)00648-1