Figure 2.

TREM2-mediated suppression of amyloid accumulation and neuritic dystrophy in the early stage of pathological development. (A) Illustration of induction paradigms for the expression of human TREM2-WT or TREM2-R47H during different stages of the amyloid development in the 5xFAD background. (B–E) Representative images (B and C) and quantification (D and E) of Aβ plaque load by immunofluorescence staining with MOAB2 antibody (B and D) and fibrillar Aβ by X-34 labeling (C and E) in the mice induced for TREM2-WT or TREM2-R47H expression during 0–3.5 mo of age. Scale bar, 1 mm. (F–H) The levels of Aβ42 in the detergent soluble (TBSX) and insoluble (GND) fractions and the Aβ40 in the insoluble (GND) fraction were detected by ELISAs in the mice expressing TREM2-WT or TREM2-R47H during 0–3.5 mo of age. (I and J) The representative images (J) and quantification (I) of dystrophic neurites by immunofluorescence staining with LAMP1 antibody in the mice induced for TREM2-WT or TREM2-R47H expression during 0–3.5 mo of age. Scale bar, 1 mm. n = 11–13 mice/group, mixed sexes. Data are shown as mean ± SEM. Mann–Whitney tests with Bonferroni correction were used for statistical analysis. P values <0.025 were considered to be statistically significant. *, P < 0.025; **, P < 0.01; N.S., not significant. (K–P) The ISF from the hippocampus of the 5xFAD mice expressing TREM2-WT (K–M) or TREM2-R47H (N–P) at 0–3.5 mo was collected via in vivo microdialysis. (K, L, N, and O) The levels of Aβ42 at baseline or after γ-secretase inhibitor treatment were quantified by ELISAs. (M and P) The half-life of Aβ42 in ISF was calculated and compared. n = 3–6 mice/group, mixed sexes. Data are shown as mean ± SEM. Two-tailed unpaired Student’s t tests were used for statistical analysis. *, P < 0.05; N.S., not significant. In D–I, L, M, O, and P, the data from male and female mice are labeled as solid and open circles, respectively.