Divergent Mechanisms in Amyloid Formation Controlled by Critical Points

Abstract

The aggregation of amyloidogenic proteins is infamous for being highly chaotic, with small variations in conditions leading to large changes in aggregation rates. We present experimental evidence that the origin of this phenomenom for a broad variety of amyloidogneic oligomers is related to the critical concentration for the formation of particular type of prefibrillar oligomer. Using chemical probes and real time solution NMR, we show that oligomers of this type reversibly form at sharply defined critical concentrations and temperatures in a manner similar to a phase transition. Similarly, the kinetics of fiber formation also show strong non-linearity near these critical points. For some amyloidogenic proteins such as IAPP, the pathway of amyloid formation switches as the critical point is approached, with aggregation initiating at different regions of the protein above and below the critical point. We also show that part of the effect of some inhibitors on amyloid aggregation is to abolish or shift the critical concentration, and map the interface between monomeric IAPP and Aβ and these aggregates.