TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques
2016/04/18 by Yaming Wang, Tyler K. Ulland, Jason D. Ulrich +14 · 889 citations
Immunology and Microbiology · Medicine · Neuroscience · #Amyloid (mycology) #Biology #Immunology #Inflammation #Inflammation biomarkers and pathways #Internal medicine #Medicine #Microglia #Neuroinflammation and Neurodegeneration Mechanisms #Neurological Disease Mechanisms and Treatments #Neuroscience #Pathology #TREM2 #Toxicity
paper · pdf · doi:10.1084/jem.20151948
published in The Journal of Experimental Medicine 213(5), 667-675 (Rockefeller University Press)
openalex publication_date 2016/04/18 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/04
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.
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