Abstract
Aggregation of amyloid β (Aβ) peptides is a significant event that underpins Alzheimer disease (AD) pathology. Aβ 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 Aβ 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 Aβ 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 Aβ 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 Aβ, which may have profound phenotypic outcomes. Our results validate previous experimental observations and provide insights into potential influence of biological interfaces in modulating Aβ aggregation pathways.
Highlights
One class of biologically important interacting partners that affect amyloid β (Aβ) pre-nucleation dynamics are the anionic surfactants such as fatty acids and lipids[33,34,35,36,37,38,39]
The results reported here by two independent methods (ROM and ensemble kinetic simulation (EKS)) reaffirm the experimental observations that fatty acids (FAs) modulate Aβ aggregation
The following significant conclusions can be drawn from this work: (a) interactions of Aβ with non-micellar FAs (FAn) generate predominantly high molecular weight, on-pathway aggregates. (b) Interactions of Aβ with FAs near the latter’s critical micelle concentrations (CMCs) (FApm) generate predominantly low molecular weight oligomers (12–24 mers) along off-pathway along with some minor quantities of on-pathway fibrils. (c) Interactions of Aβ with high concentrations of FAs (FAm; above their CMCs) exclusively generate off-pathway [4,5] mer oligomers without any fibrils suggesting that the on-pathway was completely turned off
Summary
One class of biologically important interacting partners that affect Aβ pre-nucleation dynamics are the anionic surfactants such as fatty acids and lipids[33,34,35,36,37,38,39]. The switching of stabilities is revealed by α3, which, by its definition, contains the ratio of the forward to backward rate constants for this reaction, as well as the fatty acid concentration which enhances the formation of the off-pathway species.
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