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Updated: Mar 22, 2026
Cell-based Assay to Study Antibody-mediated Tau Clearance by Microglia
Published on: November 9, 2018
TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques
Yaming Wang1, Tyler K Ulland2, Jason D Ulrich3
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110 Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285.
Abstract:
Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial receptor that recognizes changes in the lipid microenvironment, which may occur during amyloid β (Aβ) accumulation and neuronal degeneration in Alzheimer's disease (AD). Rare TREM2 variants that affect TREM2 function lead to an increased risk of developing AD. In murine models of AD, TREM2 deficiency prevents microglial clustering around Aβ deposits. However, the origin of myeloid cells surrounding amyloid and the impact of TREM2 on Aβ accumulation are a matter of debate. Using parabiosis, we found that amyloid-associated myeloid cells derive from brain-resident microglia rather than from recruitment of peripheral blood monocytes. To determine the impact of TREM2 deficiency on Aβ accumulation, we examined Aβ plaques in the 5XFAD model of AD at the onset of Aβ-related pathology. At this early time point, Aβ accumulation was similar in TREM2-deficient and -sufficient 5XFAD mice. However, in the absence of TREM2, Aβ plaques were not fully enclosed by microglia; they were more diffuse, less dense, and were associated with significantly greater neuritic damage. Thus, TREM2 protects from AD by enabling microglia to surround and alter Aβ plaque structure, thereby limiting neuritic damage.
Insights
Triggering receptor expressed on myeloid cells 2 (TREM2) deficiency in Alzheimer's disease (AD) models leads to more diffuse amyloid plaques and greater neuritic damage. TREM2 enables microglia to surround plaques, protecting against neurodegeneration.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial receptor implicated in Alzheimer's disease (AD) pathogenesis.
- TREM2 variants are associated with increased AD risk, but its precise role in amyloid-beta (Aβ) pathology and microglial response remains debated.
- The origin of myeloid cells at amyloid deposits and TREM2's impact on Aβ accumulation require clarification.
Purpose of the Study:
- To investigate the origin of myeloid cells surrounding amyloid plaques in AD.
- To determine the impact of TREM2 deficiency on Aβ plaque formation and associated neuropathology.
- To elucidate the protective mechanisms of TREM2 in Alzheimer's disease.
Main Methods:
- Parabiosis experiments were conducted to trace the origin of amyloid-associated myeloid cells.
- 5XFAD mouse model of AD was used to examine Aβ plaque pathology in TREM2-deficient and -sufficient mice at early disease stages.
- Histological analysis assessed Aβ plaque morphology, microglial clustering, and neuritic damage.
Main Results:
- Amyloid-associated myeloid cells were found to originate from brain-resident microglia, not peripheral monocytes.
- TREM2 deficiency did not alter the initial rate of Aβ accumulation.
- In TREM2-deficient mice, Aβ plaques were more diffuse, less dense, and exhibited significantly increased neuritic damage compared to controls.
Conclusions:
- TREM2 plays a critical role in microglial engagement with Aβ plaques.
- Microglial TREM2 function is essential for altering Aβ plaque structure and mitigating associated neurotoxicity.
- TREM2-mediated microglial responses protect against neuritic damage, highlighting its therapeutic potential in Alzheimer's disease.
