Figure 1.

Model. (A) Signaling network of Aβ fibrillization. sAβ (S) is produced by the mean rate R and cleared by efflux through the CSF. S transforms to fAβ (F) by nucleation and polymerization. Microglia (M) clear S and F through macropinocytosis and phagocytosis, respectively. The blocking arrows from microglia (M) to S and F represent that microglia clear S and F by macropinocytosis and phagocytosis, respectively. (B) Estimation of the nucleation and polymerization rate constants according to the ThT experiments conducted by Cohen et al. (44). The points and lines correspond to the experimental data and the model, respectively. The colors in the main plot correspond to the marker colors in the inset. A reduced model is used for the estimation, in which only an initial concentration for sAβ (S_o) and the nucleation k_n and polymerization rate constant k_p are taken into account, i.e., Eqs. 1 and 2 reduce to $\dot{S}$ = −k_pSF − k_nS² and F = S_o − S. The parameters are estimated through the differential evolution algorithm (68) with logarithmic weight 1/logS_o on the cost function to weigh lower concentrations more because the physiological concentrations are orders of magnitude lower than the experimental concentrations. k_n = 2.2 × 10⁻¹μM⁻¹ ⋅ day⁻¹ and k_p 2.1 × 10¹μM⁻¹ ⋅ day⁻¹. The proposed minimal model is able to catch the fibrillization behavior quite well. To see this figure in color, go online.