Fig. 1
From: Trem2 deficiency differentially affects phenotype and transcriptome of human APOE3 and APOE4 mice
Trem2 deficiency impacts cognition, plaque compaction, and microglia recruitment in APP/E3 and APP/E4 mice. a Schematic timeline showing groups and experimental procedures of 6.5-month-old mice used for behavioral, histological, and transcriptional analysis (Figs. 1, 4, 5, and 6). b Novel object recognition (NOR), and Contextual fear conditioning. Analysis by two-way ANOVA showed no interaction between APOE isoform and Trem2 status and a significant main effect of APOE isoform (F (1, 49) = 13.28, p < 0.01) and Trem2 status (F (1, 49) = 11.06, p < 0.01) for NOR (a, b), and Contextual fear conditioning (c, d) APOE isoform effect (F (1, 50) = 11.39, p < 0.01) and Trem2 status (F (1,50) = 10.86, p < 0.01). ** p < 0.01; * p < 0.05, Sidak multiple comparisons test. n = 6–14 mice per group. For APP mice n = 6–7 mice/genotype/sex (12–14 mice/genotype). For non-APP mice, n = 4–7 mice/genotype/sex (8–14 mice/genotype). On the graphs, red symbols indicate female and black symbols indicate male mice. c Representative images of X34 and OC labeled amyloid deposits showing core-bound and non-core bound OC. d Bar plot depicting the ratio of non-core bound OC to total OC. n = 15–26 mice per group. e Representative images of glial cells (Iba1+ microglia and GFAP+ astrocytes) recruited to amyloid plaques. f Bar plots depicting the number of microglia nuclei within 60 μm of plaque border. g Bar plots depicting the number of astrocyte nuclei within 60 μm of plaque border. n = 80–120 plaques from 6 mice per group. h Representative images of X34 and LAMP1 label showing neuronal dystrophy surrounding amyloid deposits. X34 is shown as a blue region of interest defined by NIS elements thresholding. i Bar plot depicting the area of plaque-associated LAMP1 staining. Analysis by two-way ANOVA showed no interaction between APOE isoform and Trem2 status and a significant main effect of APOE isoform (F (1, 476) = 25.41, p < 0.0001) and Trem2 status (F (1, 476) = 4.99, p < 0.05) for LAMP1 area. Sidak multiple comparison test found no difference in plaque-associated LAMP1 staining area between APP/E3 vs APP/E3/Trem2ko or APP/E4 vs APP/E4/Trem2ko. n = 120 plaques from 4 mice per group. j Representative images of plaque-associated APOE (green) and TR (red) staining to visualize compact amyloid plaques. k Bar plots showing the area of APOE staining that surrounds TR positive amyloid plaques. n = 874–2719 plaques from 4 to 6 mice per group. l Bar plots depicting Apoe gene expression as identified by RNA-seq, which closely follows the pattern of plaque-associated APOE protein levels. For histological analyses, one-way ANOVA was used followed by Tukey’s multiple comparison test. m Representative images of FISH analyses of gene expression near amyloid plaques (Tmem119 – green, Apoe – Pink, Nuclei – Blue). n Bar plot depicting the Apoe gene expression within Tmem119-positive microglia cells. The intensity of Apoe FISH signal was normalized to the number of Tmem119-positive microglial cells. n = 279–313 microglia per group. Bars represent mean ± SEM, with all red bars = APP/E3, orange = APP/E3/Trem2ko, purple = APP/E4, and blue = APP/E4/Trem2ko. *** p < 0.001; ** p < 0.01; * p < 0.05; NS = No Signifincace