MassIVE MSV000085698

Partial Public PXD020240

Multi-omic comparison of Alzheimers variants in human ESC-derived microglia reveals convergence at APOE

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Description

Variations in many genes linked to sporadic Alzheimers disease (AD), show abundant expression in microglia, however, relationships between these genes remain largely elusive. Here, we establish isogenic human ES-derived microglia-like cell lines (hMGLs) harboring AD variants in CD33, INPP5D, SORL1 and TREM2 loci, and curate a comprehensive atlas comprising ATACseq, ChIPseq, RNAseq 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 upregulation of APOE as a convergent pathogenic node. We also observe cross-regulatory relationships between SORL1 and TREM2, where SORL1R744X hMGLs induce TREM2 expression to enhance APOE expression. AD-associated SORL1 and TREM2 mutations also impaired hMGL A-beta uptake in an APOE-dependent manner in vitro, and attenuated A-beta uptake/clearance in mouse AD brain xenotransplants. Utilizing 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 [doi:10.25345/C52X73] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: human microglia ; APOE ; SORL1 ; TREM2 ; Alzheimers disease

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Principal Investigators:
(in alphabetical order) 		Timothy Y. Huang, Sanford Burnham Prebys Medical Discovery Institute, United States
Submitting User: alexcampos
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