TREM2 Alzheimer's variant R47H causes similar transcriptional dysregulation to knockout, yet only subtle functional phenotypes in human iPSC-derived macrophages.

Alzheimer's Research & Therapy
Hazel Hall-RobertsSally A. Cowley

Abstract

TREM2 is a microglial cell surface receptor, with risk mutations linked to Alzheimer's disease (AD), including R47H. TREM2 signalling via SYK aids phagocytosis, chemotaxis, survival, and changes to microglial activation state. In AD mouse models, knockout (KO) of TREM2 impairs microglial clustering around amyloid and prevents microglial activation. The R47H mutation is proposed to reduce TREM2 ligand binding. We investigated cell phenotypes of the R47H mutant and TREM2 KO in a model of human microglia, and compared their transcriptional signatures, to determine the mechanism by which R47H TREM2 disrupts function. We generated human microglia-like iPSC-macrophages (pMac) from isogenic induced pluripotent stem cell (iPSC) lines, with homozygous R47H mutation or TREM2 knockout (KO). We firstly validated the effect of the R47H mutant on TREM2 surface and subcellular localization in pMac. To assess microglial phenotypic function, we measured phagocytosis of dead neurons, cell morphology, directed migration, survival, and LPS-induced inflammation. We performed bulk RNA-seq, comparing significant differentially expressed genes (DEGs; p < 0.05) between the R47H and KO versus WT, and bioinformatically predicted potential upstream regula...Continue Reading

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Citations

Dec 15, 2020·Progress in Neurobiology·Hannah FranklinRickie Patani
Sep 3, 2021·The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry·Wenhui Qu, Ling Li

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Datasets Mentioned

BETA
GSE89189

Methods Mentioned

BETA
RNA-seq
PCR
FACS
protein assay
ELISA
electron microscopy
ELISAs
PCA
GTPase
flow cytometry

Software Mentioned

Ingenuity Pathway Analysis
gcBias
ggplot2
pMac
ClusterProfiler
Ingenuity Pathways Analysis ( IPA )
ScreenWorks
R library
R
Ensembl

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