Kinetic modeling of nucleated polymerization of amyloid beta and anti-amyloidogenic activity of bromocriptine in Alzheimer's disease

Abstract

Nucleated polymerization of amyloid beta protein (Aβ) in Alzheimer’s disease (AD) is one of the important steps. It consists of the formation of nuclei from Aβ monomers which further polymerizes to form the mature fibrils. Reactive oxygen species (ROS) is believed to be a major factor for abnormal Aβ aggregation. However, its exact interplay with amyloid beta species is still unknown. Moreover, for therapeutic purposes in AD, understanding the aggregation mechanism becomes more crucial, when an inhibitor is introduced into the Aβ aggregation process. Herein, a previously reported model is significantly extended with ROS initiated kinetic model considering both the nucleated aggregation of amyloid beta and the anti-amyloidogenic activities of the bromocriptine inhibitor. Associated parameters of the proposed model are tuned with the experimental data. The tuned model is validated on other sets of experimental data on fibril concentrations available on different monomer concentrations and a different bromocriptine concentration. The model predicted fibril concentration values show good correlation with the experimental data. Sensitivity analyses are conducted to check reliability and robustness of the proposed model, and acceptability of the tuned model parameters. The proposed model may be useful to gain therapeutic insights, and their mechanisms of action with Aβ species.