A game-theoretic approach to deciphering the dynamics of amyloid-ß aggregation along competing pathways.

Aggregation of amyloid-ß (Aß) peptides is a significant event that underpins Alzheimer's disease (AD). Aß aggregates, especially the low-molecular weight oligomers, are the primary toxic agents in AD pathogenesis. Therefore, there is increasing interest in understanding their formation and behaviour. In this paper, we use our previously established results on heterotypic interactions between Aß and fatty acids (FAs) to investigate off-pathway aggregation under the control of FA concentrations to develop a mathematical framework that captures the mechanism. Our framework to define and simulate the competing on- and off-pathways of Aß aggregation is based on the principles of game theory. Together with detailed simulations and biophysical experiments, our models describe the dynamics involved in the mechanisms of Aß aggregation in the presence of FAs to adopt multiple pathways. Specifically, our reduced-order computations indicate that the emergence of off- or on-pathway aggregates are tightly controlled by a narrow set of rate constants, and one could alter such parameters to populate a particular oligomeric species. These models agree with the detailed simulations and experimental data on using FA as a heterotypic partner to modulate the temporal parameters. Predicting spatio-temporal landscape along competing pathways for a given heterotypic partner such as lipids is a first step towards simulating scenarios in which the generation of specific 'conformer strains' of Aß could be predicted. This approach could be significant in deciphering the mechanisms of amyloid aggregation and strain generation, which are ubiquitously observed in many neurodegenerative diseases.

Fatty Acid Concentration and Phase Transitions Modulate Aß Aggregation Pathways.

Aggregation of amyloid ß (Aß) peptides is a significant event that underpins Alzheimer disease (AD) pathology. Aß aggregates, especially the low-molecular weight oligomers, are the primary toxic agents in AD and hence, there is increasing interest in understanding their formation and behavior. Aggregation is a nucleation-dependent process in which the pre-nucleation events are dominated by Aß homotypic interactions. Dynamic flux and stochasticity during pre-nucleation renders the reactions susceptible to perturbations by other molecules. In this context, we investigate the heterotypic interactions between Aß and fatty acids (FAs) by two independent tool-sets such as reduced order modelling (ROM) and ensemble kinetic simulation (EKS). We observe that FAs influence Aß dynamics distinctively in three broadly-defined FA concentration regimes containing non-micellar, pseudo-micellar or micellar phases. While the non-micellar phase promotes on-pathway fibrils, pseudo-micellar and micellar phases promote predominantly off-pathway oligomers, albeit via subtly different mechanisms. Importantly off-pathway oligomers saturate within a limited molecular size, and likely with a different overall conformation than those formed along the on-pathway, suggesting the generation of distinct conformeric strains of Aß, which may have profound phenotypic outcomes. Our results validate previous experimental observations and provide insights into potential influence of biological interfaces in modulating Aß aggregation pathways.