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

J Exp Med 2020 Dec;217(12)

Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1084/jem.20200474DOI Listing
December 2020

Publication Analysis

Top Keywords

sorl1 trem2
16
human esc-derived
8
trem2
5
expression
5
convergent pathogenic
4
pathogenic node
4
expression datasets
4
apoe convergent
4
up-regulation apoe
4
indicates up-regulation
4
node observe
4
datasets indicates
4
induce trem2
4
trem2 sorl1r744x
4
sorl1r744x hmgls
4
relationships sorl1
4
cross-regulatory relationships
4
epigenetic expression
4
observe cross-regulatory
4
hmgls induce
4

Altmetric Statistics

Similar Publications