Effects of Crowding Agents and Volume Exclusion on Amyloid Beta Fibrillation

Abstract

Several common neurodegenerative disorders can be attributed to pathological protein aggregation, including Alzheimer Disease, the most common form of dementia. It is known that macromolecular crowding promotes protein associations, including the formation of complexes and aggregates, both through theoretical works and in vitro. Therefore a possible contributing factor in the onset of Alzheimer Disease and other amyloidoses could be an increase in crowding content inside cells. In this work, we carried out computational simulations demonstrating the promotion of a generalized aggregation reaction model for amyloid beta fibrillation by increasing crowding agent concentration within biologically relevant values. In our in silico experiment, we implemented simulations with emulating the biophysico chemical properties of the intracellular environment, including nonspecific affinity of reacting species to crowding agents, varying size and shape of crowding agents, glymphatic removal and new synthesis of reactants, and others, demonstrating conditions in which aggregation can be more highly dependent on crowding agent concentration. Our work suggests loss of cellular crowding or volume control as a precursor to pathological aggregation.