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

TL;DR

This paper introduces a comprehensive model and simulation approach for studying protein aggregation, including membrane-assisted pathways, to better understand Alzheimer's disease mechanisms and reconcile experimental differences.

Contribution

The paper presents a novel model and simulation methodology that captures multiple aggregation pathways and scales, providing insights into aggregation dynamics relevant to Alzheimer's disease.

Findings

Identified parameter ranges leading to monomer depletion similar to Alzheimer's observations.

Demonstrated diverse aggregation behaviors based on reaction parameters and concentrations.

Highlighted challenges in relating in-vitro and in-vivo experimental results.

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.