Abstract

Genome-wide association studies have reported that, amongst other microglial genes, variants in TREM2 can profoundly increase the incidence of developing Alzheimer’s disease (AD). We have investigated the role of TREM2 in primary microglial cultures from wild type mice by using siRNA to decrease Trem2 expression, and in parallel from knock-in mice heterozygous or homozygous for the Trem2 R47H AD risk variant. The prevailing phenotype of Trem2 R47H knock-in mice was decreased expression levels of Trem2 in microglia, which resulted in decreased density of microglia in the hippocampus. Overall, primary microglia with reduced Trem2 expression, either by siRNA or from the R47H knock-in mice, displayed a similar phenotype. Comparison of the effects of decreased Trem2 expression under conditions of lipopolysaccharide (LPS) pro-inflammatory or IL-4 anti-inflammatory stimulation revealed the importance of Trem2 in driving a number of the genes up-regulated in the anti-inflammatory phenotype. RNA-seq analysis showed that IL-4 induced the expression of a program of genes including Arg1 and Ap1b1 in microglia, which showed an attenuated response to IL-4 when Trem2 expression was decreased. Genes showing a similar expression profile to Arg1 were enriched for STAT6 transcription factor recognition elements in their promoter, and Trem2 knockdown decreased levels of STAT6. LPS-induced pro-inflammatory stimulation suppressed Trem2 expression, thus preventing TREM2’s anti-inflammatory drive. Given that anti-inflammatory signaling is associated with tissue repair, understanding the signaling mechanisms downstream of Trem2 in coordinating the pro- and anti-inflammatory balance of microglia, particularly mediating effects of the IL-4-regulated anti-inflammatory pathway, has important implications for fighting neurodegenerative disease.

Highlights

  • Genome-wide association studies (GWAS) continue to reveal variants in immune/microglia-related genes that significantly increase the risk of developing Alzheimer’s disease (AD)

  • PT We aimed to investigate the effects of the Trem2 R47H variant associated with AD in I microglia and compare these to acute Trem2 ‘loss-of-function’ using siRNA in R microglia

  • The primary U effect in these Trem2 R47H KI mice was a substantial and chronic gene dose-related N decrease in Trem2 expression in hippocampal tissue from the mice (Fig. 1A)

Read more

Summary

Introduction

Genome-wide association studies (GWAS) continue to reveal variants in immune/microglia-related genes that significantly increase the risk of developing Alzheimer’s disease (AD). These genes include TREM2, CD33, ABI3, PLCG2. In 2013, two independent GWAS studies (2, 4) E highlighted a rare variant rs75932628-T in exon 2 of the TREM2 gene, causing an R arginine-to-histidine substitution at amino acid position 47 (R47H), to be highly R significantly associated with increased AD risk. The risk from this variant has a CO comparable effect size to the APOEε4 allele (around 3-fold increased AD risk; (4, 19UN22). All of the TREM2 genetic linkage studies with neurodegenerative diseases suggest an important contribution of impaired or decreased TREM2 function in regulating microglial functions contributing to disease

Objectives
Methods
Results
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call