Related Experiment Video
Updated: Jul 30, 2025
In vitro Quantitative Imaging Assay for Phagocytosis of Dead Neuroblastoma Cells by iPSC-Macrophages
Published on: February 14, 2021
The TREM2 H157Y Variant Influences Microglial Phagocytosis, Polarization, and Inflammatory Cytokine Release
Xin-Xin Fu1,2, Shuai-Yu Chen2, Hui-Wen Lian2
1Department of Neurology, Nanjing First Hospital, China Pharmaceutical University, No.639 Longmian Road, Nanjing 211100, China.
Abstract:
Previously, we reported that H157Y, a rare coding variant on exon 3 of the triggering receptor expressed on myeloid cells 2 gene (TREM2), was associated with Alzheimer's disease (AD) risk in a Han Chinese population. To date, how this variant increases AD risk has remained unclear. In this study, using CRISPR-Cas9-engineered BV2 microglia, we tried to investigate the influence of the Trem2 H157Y variant on AD-related microglial functions. For the first time, we revealed that the Trem2 H157Y variant inhibits microglial phagocytosis of amyloid-β, promotes M1-type polarization of microglia, and facilitates microglial release of inflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α. These findings provide new insights into the cellular mechanisms by which the TREM2 H157Y variant elevates the risk of AD.
Insights
The TREM2 H157Y variant impairs microglial phagocytosis and promotes inflammation, increasing Alzheimer's disease risk. This study clarifies the cellular mechanisms behind this genetic association.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- The TREM2 gene plays a crucial role in microglial function.
- A rare variant, H157Y, in TREM2 is linked to increased Alzheimer's disease (AD) risk.
- The precise mechanisms by which TREM2 H157Y influences AD pathogenesis are not fully understood.
Purpose of the Study:
- To investigate the functional impact of the TREM2 H157Y variant on microglial cells.
- To elucidate the cellular mechanisms underlying the association between TREM2 H157Y and Alzheimer's disease risk.
Main Methods:
- Utilized CRISPR-Cas9 gene editing technology to engineer BV2 microglia with the Trem2 H157Y variant.
- Assessed microglial phagocytic activity against amyloid-beta.
- Analyzed microglial polarization status (M1-type).
- Quantified the release of key inflammatory cytokines (IL-1β, IL-6, TNF-α).
Main Results:
- The TREM2 H157Y variant significantly inhibits the phagocytosis of amyloid-beta by microglia.
- This variant promotes a pro-inflammatory M1-type polarization of microglia.
- Microglia expressing the H157Y variant exhibit increased release of inflammatory cytokines, including IL-1β, IL-6, and TNF-α.
Conclusions:
- The TREM2 H157Y variant disrupts essential microglial functions critical for Alzheimer's disease pathology.
- These functional deficits include impaired amyloid-beta clearance and heightened inflammatory responses.
- Findings provide novel cellular insights into how TREM2 H157Y elevates Alzheimer's disease risk.
More Related Videos
10:40Immunofluorescence Staining Using IBA1 and TMEM119 for Microglial Density, Morphology and Peripheral Myeloid Cell Infiltration Analysis in Mouse Brain
Published on: October 27, 2019
07:19Assessing Retinal Microglial Phagocytic Function In Vivo Using a Flow Cytometry-based Assay
Published on: October 18, 2016
