Multi-omic comparison of Alzheimer’s variants in human ESC–derived microglia reveals convergence at APOE

• DOI: 10.1084/jem.20200474
• Publication Date: 2020-09-17T13:42:15Z
• Authors: Tongfei Liu; Bing Zhu; Yan Liu; Xiaoming Zhang; Jun Yin; Xiaoguang Li; LuLin Jiang; Andrew P. Hodges; Sara Brin Rosenthal; Lisa Zhou; Joel Yancey; Amanda McQuade; Mathew Blurton-Jones; Rudolph E. Tanzi; Timothy Y. Huang; Huaxi Xu
• Keywords: 0301 basic medicine; Aging; Biomedical and clinical sciences; Proteome; Human Embryonic Stem Cells; Neurodegenerative; Alzheimer's Disease; Medical and Health Sciences; Transgenic; Technical Advances and Resources; Epigenesis, Genetic; Mice; Models; 2.1 Biological and endogenous factors; Gene Regulatory Networks; Heterologous; Brain; Cell Differentiation; Chromatin; Up-Regulation; Neurological; Gene Targeting; Microglia; Signal Transduction; 570; Immunology; 610; Mice, Transgenic; Models, Biological; Cell Line; 03 medical and health sciences; Apolipoproteins E; Genetic; Phagocytosis; Alzheimer Disease; Health Sciences; Acquired Cognitive Impairment; Genetics; Animals; Humans; Transplantation; Amyloid beta-Peptides; Biomedical and Clinical Sciences; Human Genome; Neurosciences; Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD); Health sciences; Genetic Variation; Biological; Brain Disorders; Genetic Loci; Mutation; Dementia; Mutant Proteins; Transcriptome; Epigenesis

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.