Model for competing pathways in protein-aggregation: role of membrane bound proteins

Abstract

Motivated by the biologically important and complex phenomena of A\beta\ peptide aggregation in Alzheimer's disease, we introduce a model and simulation methodology for studying protein aggregation that includes extra-cellular aggregation, aggregation on the cell-surface assisted by a membrane bound protein, and in addition, supply, clearance, production and sequestration of peptides and proteins. The model is used to produce equilibrium and kinetic-aggregation phase diagrams for aggregation onset and of reduced stable A\beta\ monomer concentrations due to aggregation. The methodology we implemented permits modeling of a phenomenon involving orders of magnitude differences in time scales and concentrations which can be retained in the simulation. We demonstrate how to identify ranges of parameter values that give monomer concentration depletion upon aggregation similar to that observed in Alzheimer's disease. We show how very different behavior can be obtained as reaction parameters and protein concentrations vary, and discuss the difficulty reconciling results of experiments from two vastly different concentration regimes. The latter is an important general issue in relating in-vitro and mice based experiments to humans.