Fig. 2. Brain Aβ after short-term and chronic BACE1 inhibition.

Brain Aβ (human Aβx–40 and Aβx–42 assessed by immunoassays) in APPPS1 mice. a Brain Aβ at baseline and after short-term BI treatment in ‘young’, ‘adult’, and ‘aged’ mice (see Fig. 1 and Supplementary Fig. 1a for treatment groups and number of mice per group). Short-term BI treatment caused a significant decrease in brain Aβ compared to the respective age-matched control groups, and was below baseline in the ‘adult’ and ‘aged’ groups (ANOVA, ‘young’: F(2, 27) = 547.1; ‘adult’: F(2, 26) = 35.31; ‘aged’: F(2, 37) = 10.33, all P < 0.001; post hoc Tukey’s multiple comparisons, *P < 0.05, **P < 0.01, ***P < 0.001). b Brain Aβ levels in the young-chronic and adult-chronic groups were normalized to the 21.5 mo-old control mice in the 3-month treatment group shown in a. Two-tailed unpaired t-tests revealed significantly lower brain Aβ levels in the BI-treated mice (‘young-chronic’: t(26)=30.69; ‘adult-chronic’: t(24) = 17.99, both ***P < 0.001). c Cross-sectional curves of the means of brain Aβ from a and b show the increase of brain Aβ in the control mice (gray line), consistent with previous studies shown in Fig. 1a. When initiated before Aβ deposition was present (i.e., at 1.5 mo of age), BI treatment markedly (>90%) inhibited the deposition of Aβ for both the short-term and chronic treatments. When initiated in amyloid-laden mice, the BI treatment led to an Aβ reduction below baseline. Since the chronic treatments are, in a sense, an extension of the 3-month treatments, the lines are drawn from the 3-month treatments to the end of the chronic treatments. All data are represented as group means ± s.e.m. Open circles are males, filled circles females; no effect of sex was found (see Methods). Similar data were obtained when Aβ deposition was assessed by immunostaining, see Supplementary Fig. 2.