O2‐07‐03: Regulatory T Cells Delay Disease Progression in Alzheimer's‐Like Pathology

in the lipid microenvironment, which may result from Ab accumulation and neuronal degeneration in Alzheimer’s disease (AD). Rare TREM2 variants that impair lipid/lipoprotein recognition lead to an increased risk of developing AD. In murine models of AD, TREM2 deficiency prevents Iba-1 myeloid cells clustering around Ab deposits. However, the origin of these cells and their impact on Ab accumulation and Ab-associated neurotoxicity are a matter of debate. Methods:Using parabiosis, we determined the contribution of peripheral blood monocytes to the pool of myeloid cells that are associated with Ab deposits in 5XFAD and APPPS1-21 mice. To understand the role ofmicroglia inAb accumulation andAb-associated neurotoxicity, we examined the impact of TREM2 deficiency at the onset of Abrelated pathology in 5XFAD mice. Results:We found that amyloidassociated myeloid cells were derived from expansion of brain-resident microglia rather than from recruitment of peripheral monocytes. TREM2 deficiency impaired the clustering of microglia around amyloid plaques even at the onset of Ab-related pathology. Remarkably, morphological analysis revealed that plaques from TREM2-deficient 5XFAD mice were drastically distinct, appearing more diffuse and less dense than those from 5XFAD mice. Moreover, Ab plaques in TREM2-deficient mice were associated with significantly greater neuritic dystrophy. Conclusions:We concluded that peripheral blood monocytes have aminimumcontribution to the expansion ofmicroglia under normal physiological condition in two AD transgenic models. One mechanism via which TREM2 protects from AD is by enabling the proliferation of amyloid-associated microglia to prevent the physical diffusion of Ab deposits, thereby limiting their toxicity.