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

Abstract

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.

Differential stimulation of pluripotent stem cell-derived human microglia leads to exosomal proteomic changes affecting neurons

“…Whether the changes in exosomal protein content are due to changes in protein packaging or underlying differences in the iPS-Mg themselves was analysed in a subset of identified proteins in this study. In line with another study [60], R47H het iPS-Mg displayed an increased expression of DAM-related genes (overall Fig 2 C is confusing to the rest of the paper) which translated to basal R47H het exosomes containing higher levels of DAM-related proteins, in comparison with basal Cv exosomes ( Fig 2 ). Whilst other studies have found an increase in microglia expressing DAM genes in animals treated with LPS [39,61] this was not replicated in this study.…”

“…Whether the changes in exosomal protein content are due to changes in protein packaging or underlying differences in the iPS-Mg themselves was analysed in a subset of identified proteins in this study. In line with another study [60] [39,61] this was not replicated in this study. This could be due to differences between murine and human microglia, or the time course of the experiments.…”

APOE genotype dependent molecular abnormalities in the cerebrovasculature of Alzheimer’s disease and age-matched non-demented brains

“…Our cerebrovascular tissue showed moderate expression of glial markers, therefore some of the APOE specific effects we observed could be driving in part by changes in these cell types, which are the main producers of APOE in the brain [33]. APOE4 genotype has been demonstrated to influence the phenotypic change of astrocytes into the A1 disease phenotype, and also convert microglia into neurotoxic entities that produce proinflammatory cytokines [105,[108][109][110][111][112]. In AD, glial cell inflammation could therefore serve as critical determinants driving the immune response that contributes to the damage of cerebrovessels.…”

Microglial transcription profiles in mouse and human are driven by APOE4 and sex

“…Our findings add to a growing literature demonstrating shifts in microglial gene expression across various states and diseases, including transcriptional signatures associated with specific DAM subpopulations ( Rangaraju et al., 2018 ), with different stages of neurodegeneration ( Mathys et al., 2017 ), and with aging in both human ( Olah et al., 2018 ) and mouse ( Hammond et al., 2019 ) microglia. Recent reports have also demonstrated a role for APOE in the context of microglial gene expression ( Liu et al., 2020 ; Sala Frigerio et al., 2019 ). For instance, TREM2-dependent APOE signaling is necessary for expression of the DAM phenotype, and blocking this pathway restores homeostatic microglia while reducing neuron loss ( Krasemann et al., 2017 ).…”