Language

English

Publication Date

2-1-2024

Journal

Glia

DOI

10.1002/glia.24485

PMID

37969043

PMCID

PMC10904109

PubMedCentral® Posted Date

2-1-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Genetic findings have highlighted key roles for microglia in the pathology of neurodegenerative conditions such as Alzheimer's disease (AD). A number of mutations in the microglial protein triggering receptor expressed on myeloid cells 2 (TREM2) have been associated with increased risk for developing AD, most notably the R47H/+ substitution. We employed gene editing and stem cell models to gain insight into the effects of the TREM2 R47H/+ mutation on human-induced pluripotent stem cell-derived microglia. We found transcriptional changes affecting numerous cellular processes, with R47H/+ cells exhibiting a proinflammatory gene expression signature. TREM2 R47H/+ also caused impairments in microglial movement and the uptake of multiple substrates, as well as rendering microglia hyperresponsive to inflammatory stimuli. We developed an in vitro laser-induced injury model in neuron-microglia cocultures, finding an impaired injury response by TREM2 R47H/+ microglia. Furthermore, mouse brains transplanted with TREM2 R47H/+ microglia exhibited reduced synaptic density, with upregulation of multiple complement cascade components in TREM2 R47H/+ microglia suggesting inappropriate synaptic pruning as one potential mechanism. These findings identify a number of potentially detrimental effects of the TREM2 R47H/+ mutation on microglial gene expression and function likely to underlie its association with AD.

Keywords

Mice, Animals, Humans, Microglia, Induced Pluripotent Stem Cells, Mutation, Alzheimer Disease, Synapses, Brain, Membrane Glycoproteins, Receptors, Immunologic, Microglia, induced pluripotent stem cells, Alzheimer’s disease, neurodegeneration, triggering receptor expressed on myeloid cells 2 (TREM2), inflammation

Published Open-Access

yes

Download

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.