Fig. 4.

Characterization of the effects of set A and set B molecules on the secondary pathways of Aβ42 aggregation. (A) Kinetic aggregation profiles of a 2 μM Aβ42 solution in the presence of 10% of preformed seeds in the absence (gray) or presence of 5 M eq of bexarotene (blue), TTNPB (cyan), and UVI3003 (orchid). Under these conditions, elongation of the fibrils is the dominant mechanism. (B) Normalized growth rate constants derived from the fitted curves in A in the presence of 10% of preformed seed fibrils; these results show that set A molecules do not detectably affect the elongation rates of Aβ42 aggregation. (C) Kinetic profiles of the aggregation of a 2 μM Aβ42 solution in the presence of 10% of preformed seeds in the absence (gray) or presence of 5 M eq of MM11253 (green), adapalene (blue), and BMS493 (moss green); under these conditions, elongation of the fibrils is the dominant mechanism. (D) Normalized growth rate constants derived from the fitted curves in C in the presence of 10% of preformed seed fibrils; these results show that set B molecules affect the elongation rates of Aβ42 aggregation at 5 M eq. (E) Kinetic profiles of the aggregation of a 2 μM Aβ42 solution in the presence of 10% of preformed seeds in the absence (gray) or presence of 0.5 M eq of MM11253 (green), adapalene (blue), and BMS493 (moss green); under these conditions, elongation of the fibrils is the dominant mechanism. (F) Normalized growth rate constants derived from the fitted curves in E in the presence of 10% of preformed seed fibrils; these results show that set B molecules at 0.5 M eq do not affect the elongation rates of Aβ42 aggregation. Effect of 0.5 and 5 M eq of set A (G; bexarotene, TTNPB, and UVI3003) and set B (H; MM11253, adapalene, and BMS493) on the rates of the surface-catalyzed secondary nucleation (k₂). The rate constants were obtained from the aggregation kinetics of a 2 μM Aβ42 solution in the presence of 1%, 2%, and 5% of preformed seeds (Figs. S8 and S9), where primary nucleation is negligible and surface-catalyzed secondary nucleation contributes ∼35%, 60%, and 80%, respectively, of the total quantity of fibrils formed, according to the simulations shown in Fig. S7. The quantitative parameters were obtained from the fitted curves in Figs. S7 and S8. The observed effects could only be due to decreasing the rate constants of surface-catalyzed secondary nucleation because elongation is not affected by the compounds under these conditions.