Fig. 7
Strong inactivating PSEN1 variants exhibit delayed AAOs, relative to biochemically predicted ones, despite Aβ signatures of pathogenicity. A Aβ profiles generated by WT or extremely inactivating PSEN1s. Data presented as mean ± SD, N ≥ 3 independent experiments. B Effects of extremely inactivating PSEN1 mutations on the overall GSEC activity, using the sum of the Aβ (37 + 38 + 40 + 42 + 43) as proxy. Data is normalized to PSEN1 WT. Data presented as mean ± SD, N ≥ 3 independent experiments. Statistics: One-way ANOVA with Dunnett's post-hoc test vs WT; ****p < 0.0001, F(5, 33) = 251.9. C Efficiency of 4th enzymatic GSEC turnover of APPC99 (estimate of GSEC processivity) quantified by the Aβ(37 + 38 + 40)/(42 + 43) ratio. Data is normalised to PSEN1 WT (shown in black). The inactivating mutations are shown in purple. Data presented as mean ± SD, N ≥ 3 independent experiments. Statistical significance determined by one-way ANOVA and Dunnett's post-hoc test compared to PSEN1 WT (p < 0.05); ****p < 0.0001, (F(DFn, DFd): F (5, 39) = 2456). D Extremely inactivating PSEN1-P88L, R278I, C410Y, P433S and L435F mutations show more than a 20 year delays in AAOs, with the exception of one P433S mutation carrier (Supplementary table S3), and relative to biochemically predicted AAOs