Related Experiment Video
Updated: Feb 23, 2026
In vitro Quantitative Imaging Assay for Phagocytosis of Dead Neuroblastoma Cells by iPSC-Macrophages
Published on: February 14, 2021
TREM2 promotes Aβ phagocytosis by upregulating C/EBPα-dependent CD36 expression in microglia
Su-Man Kim1, Bo-Ram Mun1, Sun-Jun Lee1
1School of Biological Sciences and Technology, Chonnam National University, 77 Yongbong-ro, Buk-gu, Gwangju, 500-757, South Korea.
Abstract:
TREM2 plays a critical role in the alleviation of Alzheimer's disease by promoting Aβ phagocytosis by microglia, but the detailed molecular mechanism underlying TREM2-induced direct phagocytic activity of Aβ remains to be revealed. We found that learning and memory functions were improved in aged TREM2 TG mice, with the opposite effects in KO mice. The amount of phagocytosed Aβ was significantly reduced in the primary microglia of KO mice. CD36 expression in primary microglia was greater in TG than in WT mice but was substantially decreased in KO mice. The expression of C/EBPα, an upstream transcriptional activator of CD36, was also elevated in primary microglia of TG mice but decreased in KO mice. The transcription of CD36 was markedly increased by TREM2 overexpression, and this effect was suppressed by a mutation of the C/EBPα binding site on the CD36 promoter. The TREM2-induced expression of CD36 and C/EBPα was inhibited by treatment with PI3K/AKT signaling blockers, and phosphorylation of AKT was elevated in TREM2-overexpressing BV2 cells. The present study provides evidence that TREM2 is required for preventing loss of memory and learning in Alzheimer's disease by regulating C/EBPα-dependent CD36 expression and the consequent Aβ phagocytosis.
Insights
TREM2 (triggering receptor expressed on myeloid cells 2) is crucial for Alzheimer's disease. It enhances microglial phagocytosis of amyloid-beta (Aβ) by regulating CD36 expression, thereby preserving learning and memory functions.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Alzheimer's disease (AD) pathogenesis involves amyloid-beta (Aβ) accumulation.
- Microglia play a key role in clearing Aβ, and TREM2 (triggering receptor expressed on myeloid cells 2) is implicated in this process.
- The precise molecular mechanisms linking TREM2 to microglial phagocytosis of Aβ are not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanism by which TREM2 enhances microglial phagocytosis of Aβ.
- To investigate the role of TREM2 in regulating learning and memory in the context of AD.
- To identify key downstream targets and signaling pathways involved in TREM2-mediated Aβ clearance.
Main Methods:
- Utilized TREM2 transgenic (TG) and knockout (KO) mouse models.
- Assessed learning and memory functions in mice.
- Quantified Aβ phagocytosis in primary microglia.
- Measured CD36 and C/EBPα expression levels.
- Investigated CD36 promoter activity and the role of C/EBPα binding sites.
- Examined the involvement of PI3K/AKT signaling pathway.
Main Results:
- TREM2 TG mice showed improved learning and memory, while KO mice exhibited deficits.
- Aβ phagocytosis was significantly reduced in microglia from KO mice.
- TREM2 overexpression upregulated CD36 and C/EBPα expression, which was dependent on C/EBPα binding to the CD36 promoter.
- PI3K/AKT signaling pathway activation was essential for TREM2-induced CD36 and C/EBPα expression.
Conclusions:
- TREM2 is essential for preventing memory and learning loss in Alzheimer's disease.
- TREM2 regulates Aβ phagocytosis through C/EBPα-dependent CD36 expression.
- The PI3K/AKT signaling pathway mediates TREM2's effects on CD36 and C/EBPα expression, highlighting a novel therapeutic target for AD.
