Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA.
Center for Computational Biology and Bioinformatics, University of California, San Diego School of Medicine, La Jolla, CA.
J Exp Med. 2020 Dec 7;217(12). doi: 10.1084/jem.20200474.
Variations in many genes linked to sporadic Alzheimer's disease (AD) show abundant expression in microglia, but relationships among these genes remain largely elusive. Here, we establish isogenic human ESC-derived microglia-like cell lines (hMGLs) harboring AD variants in CD33, INPP5D, SORL1, and TREM2 loci and curate a comprehensive atlas comprising ATAC-seq, ChIP-seq, RNA-seq, and proteomics datasets. AD-like expression signatures are observed in AD mutant SORL1 and TREM2 hMGLs, while integrative multi-omic analysis of combined epigenetic and expression datasets indicates up-regulation of APOE as a convergent pathogenic node. We also observe cross-regulatory relationships between SORL1 and TREM2, in which SORL1R744X hMGLs induce TREM2 expression to enhance APOE expression. AD-associated SORL1 and TREM2 mutations also impaired hMGL Aβ uptake in an APOE-dependent manner in vitro and attenuated Aβ uptake/clearance in mouse AD brain xenotransplants. Using this modeling and analysis platform for human microglia, we provide new insight into epistatic interactions in AD genes and demonstrate convergence of microglial AD genes at the APOE locus.
与散发性阿尔茨海默病（AD）相关的许多基因的变异在小胶质细胞中表现出丰富的表达，但这些基因之间的关系在很大程度上仍难以捉摸。在这里，我们建立了具有 AD 变异的 CD33、INPP5D、SORL1 和 TREM2 基因座的同基因人 ESC 衍生的小胶质样细胞系（hMGL），并编纂了一个包含 ATAC-seq、ChIP-seq、RNA-seq 和蛋白质组学数据集的综合图谱。在 AD 突变 SORL1 和 TREM2 hMGL 中观察到 AD 样表达特征，而综合表观遗传和表达数据集的多组学分析表明 APOE 的上调是一个趋同的致病节点。我们还观察到 SORL1 和 TREM2 之间的交叉调节关系，其中 SORL1R744X hMGL 诱导 TREM2 表达以增强 APOE 表达。AD 相关的 SORL1 和 TREM2 突变也以 APOE 依赖的方式损害了 hMGL 的 Aβ摄取，并减弱了 AD 脑异种移植中 Aβ摄取/清除。使用这种人类小胶质细胞的建模和分析平台，我们提供了 AD 基因中上位相互作用的新见解，并证明了微胶质 AD 基因在 APOE 基因座上的会聚。
