Extended Data Fig. 1: Microscopic mechanism of inhibition.
From: Kinetic fingerprints differentiate the mechanisms of action of anti-Aβ antibodies
The action of an inhibitor can be assessed through the analysis of macroscopic aggregation curves5,9. A-C) Predicted changes to the macroscopic aggregation curve if the rate constant for one specific microscopic step is selectively reduced by a factor of 3 (marine blue), 10 (blue), 30 (cyan), 100 (green), 1000 (orange) or 10000 (red). The reference curve is calculated for 3 µM Aβ42 in 20 mM HEPES, 140 mM NaCl, 1 mM CaCl2 pH 8.018 with knk+ = 2.5.10-3 M-2s-2, k2k+ = 2.1.1013 M-3s-2, √KM = 0.25 µM; nc = 1, n2 = 2. (a) Inhibition of secondary nucleation (rate constant k2) causes little lag-phase extension but a reduction of the transition slope. This route for therapeutic intervention may substantially reduce toxicity5, and requires inhibitors that block the catalytic surface of fibrils, or bind to on-pathway oligomers to prevent their conversion to fibrils5,9,11,30. (b) Inhibition of primary nucleation (kn) causes a lag-phase prolongation with no effect on the transition steepness, thereby delaying the generation of oligomeric species through secondary nucleation. This requires compounds that bind Aβ monomers, nuclei or other oligomers9,12,30,31. (c). Inhibition of elongation (k+) causes both a lag-phase extension and a reduction in transition slope5,9, an effect that may increase toxicity over time5. When the ends of fibrils are blocked, a larger fraction of the monomers bind to their sides, where secondary nucleation and oligomer generation is catalyzed. The macroscopic curves are sensitive to rate constant products (knk+ and k2k+); precisely the same effect as displayed in C can arise if kn and k2 are reduced in parallel by the same factor. (d–f) Total nucleation rate underlying each trace in panel A, B and C, respectively.
