Fig 2: TREM2R47H‐BMC transplantation impaired monocytic Aβ phagocytosis in AD mice. (A) Schematic diagram of generating a specific mouse model and results of chimerism. (B) Statistics of the number of CD115+ and CD11b+ cells responding to Aβ and mean fluorescence intensity. (C) Blood Aβ40 and Aβ42 levels of AD‐TWt→Wt, AD‐TWt→Wt, and AD‐TR47H→Wt mice. (D) Correlation between blood total Aβ levels and the ability of monocytic Aβ phagocytosis. n = 8 per group for Figure A–C; n = 24 for Figure D. *p < 0.05, **p < 0.01. The error bar in C is the SEMs. Aβ, amyloid‐β; AD‐TWt, AD mice carrying the Wt TREM2 gene; AD‐TWt→W, AD mice carrying the Wt TREM2 gene that received BMCs from AD mice carrying the Wt TREM2 gene; AD‐TR47H→Wt, AD mice carrying the Wt TREM2 gene that received BMCs from AD mice carrying the R47H mutation in the TREM2 gene; ns, no statistical significance; BMC, bone marrow cells; Wt, wild‐type.

Fig 3: TREM2R47H‐BMC transplantation aggravated the Aβ burden in AD mice. (A) Immunostaining and quantification of Aβ plaques stained with the 6E10 antibody and Congo red in the neocortex and hippocampus. (B) Comparison of Aβ40 and Aβ42 levels in the TBS, SDS and FA fractions of brain. (C–E) Representative western‐blotting images and quantitative analysis of the levels of APP‐metabolizing enzymes, Aβ‐degrading enzymes and Aβ‐transporting receptors in brain homogenates. n = 8 per group; *p < 0.05. The scale bar in A is 500 #x000B5;m. The error bars are the SEMs. Aβ, amyloid‐β; AD‐TWt, AD mice carrying the Wt TREM2 gene; AD‐TWt→Wt, AD mice carrying the Wt TREM2 gene that received BMCs from AD mice carrying the Wt TREM2 gene; AD‐TR47H→Wt, AD mice carrying the Wt TREM2 gene that received BMCs from AD mice carrying the R47H mutation in the TREM2 gene; ns, no statistical significance; BMC, bone marrow cells; Wt, wild‐type.

Fig 4: Effect of the TREM2R47H mutation on monocytic Aβ phagocytosis. (A) Schematic diagram of investigation of the Aβ uptake by blood monocytes in the context of mixing CD45.2‐TREM2R47H and CD45.1‐TREM2Wt PBMCs. (B) Representative flow‐cytometric images of CD115+ and CD11b+ monocytes scavenging Aβ. (C) Statistics of the proportion of CD115+ and CD11b+ cells in response to Aβ and mean fluorescence intensity. (D) Schematic diagram of investigation of the Aβ uptake by CD115+ monocytes in the context of mixing CD45.2‐ TREM2R47H‐and TREM2Wt‐CD115+ cells. (E) Representative flow‐cytometric images of CD115+ and CD11b+ monocytes scavenging Aβ. F. Statistics of the proportion of CD115+ and CD11b+ cells responding to Aβ and mean fluorescence intensity. n = 6 per group, ***p < 0.001, ****p < 0.0001. The error bars are the SEMs. Aβ, amyloid‐β; PBMCs, peripheral blood mononuclear cells; TREM2Wt, Wt TREM2 gene; TREM2R47H, R47H mutation in the TREM2 gene; Wt, wild‐type.

Fig 5: TREM2R47H‐BMC transplantation exacerbated AD‐type pathologies in AD mice. (A) Immunostaining and quantification of astrocytes and microglia with the GFAP antibody and the CD68 antibody in the neocortex and hippocampus. (B–C) Representative immunofluorescent images and quantification of neurons (NeuN, red) and dendrites (Map2, green) in the CA1 region of the hippocampus and neural apoptosis (caspase 3, green) in the CA3 region of the hippocampus. (D) Representative immunostaining images and quantification of the levels of PT231, PS199, and Tau46 expression. (E) Representative western‐blotting images and quantification of synaptic proteins (PSD95, SYN, SNAP25, and VAMP1). n = 8 per group; *p < 0.05; ***p < 0.001. The scale bar in A is 500 #x000B5;m, and the scale bar in B is 50 #x000B5;m. The error bars are the SEMs. AD, Alzheimer's disease; AD‐TWt, AD mice carrying the Wt TREM2 gene; AD‐TWt→W, AD mice carrying the Wt TREM2 gene that received BMCs from AD mice carrying the Wt TREM2 gene; AD‐TR47H→Wt, AD mice carrying the Wt TREM2 gene that received BMCs from AD mice carrying the R47H mutation in the TREM2 gene; BMC, bone marrow cells; PSD95, postsynaptic protein‐95; SNAP25, anti‐ synaptosomal‐associated protein of 25 kDa; Wt, wild‐type.