Fig. 2

Insoluble Aβ42 and Aβ40 levels in CatD-KO, CatD-HET, and CatD-WT brains. a, b Levels of insoluble, endogenous brain Aβ42 (a) and Aβ40 (b) in CatD-KO, CatD-HET, and CatD-WT mice as a function of age. Note that levels of both Aβ species are markedly increased in CatD-KO, but not in CatD-HET, mice relative to WT controls at all ages examined. Data are mean ± SEM for 4–6 replicates per group. ^†p < 0.01; ^‡p < 0.001; ^#p < 0.0001. c Insoluble Aβ42/40 ratios are significantly increased in CatD-KO mice, but not NEP-KO, IDE-KO, or NEP/IDE-DKO mice, relative to their respective WT controls. Data are mean ± SEM for 28–30 replicates per group for CatD-KO and CatD-WT mice and 6–11 replicates per group for the other genotypes. ^#p < 0.0001. d, e Percent increases in insoluble, endogenous brain Aβ42 (d) and Aβ40 (e) in 15-day-old and 26-day-old CatD-KO mice as compared to 26-day-old NEP-KO, IDE-KO, and NEP/IDE double-knockout (DKO) mice, all normalized to respective WT controls. Note that 26-day-old CatD-KO mice exhibit significantly higher increases in insoluble Aβ42 and Aβ40 above their WT controls than age-matched mice lacking NEP, IDE, or both NEP and IDE. Data are mean ± SEM for 4–6 replicates per group. *p < 0.05; ^†p < 0.01; ^‡p < 0.001; ^#p < 0.0001. f Intracellular endogenous Aβ42 accumulation occurs in CatD-KO mice by 3 weeks of age. Shown is immunohistochemical staining of a 26-day-old CatD-KO mouse and age-matched WT control with an anti-Aβ42 end-specific antibody [31]. Additional immunohistochemical characterization is provided in Supp. Fig. S4