TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques

Triggering receptor expressed on myeloid cells 2 ( TREM2) is a microglial receptor that recognizes changes in the lipid microenvironment, which may occur during amyloid beta (A beta) 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 A beta deposits. However, the origin of myeloid cells surrounding amyloid and the impact of TREM2 on A beta 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 A beta accumulation, we examined A beta plaques in the 5XFAD model of AD at the onset of A beta-related pathology. At this early time point, A beta accumulation was similar in TREM2-deficient and -sufficient 5XFAD mice. However, in the absence of TREM2, A beta 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 A beta plaque structure, thereby limiting neuritic damage.