General integrated rate law for complex self-assembly reactions reveals the mechanism of amyloid-beta co-aggregation

TL;DR

This paper introduces a general integrated rate law derived from symmetry mathematics, enabling detailed kinetic analysis of complex protein self-assembly and co-aggregation mechanisms relevant to Alzheimer's disease.

Contribution

It presents a novel, broadly applicable rate law for complex self-assembly reactions, applied here to elucidate amyloid-beta co-aggregation mechanisms.

Findings

Abeta42 fibril surfaces catalyze co-oligomer formation.

Co-oligomers accelerate formation of other Abeta fibrils.

Abeta42 fibril formation is inhibited by co-aggregation processes.

Abstract

Analyzing kinetic experiments on protein aggregation using integrated rate laws has led to numerous advances in our understanding of the fundamental chemical mechanisms behind amyloidogenic disorders such as Alzheimer's and Parkinson's diseases. However, the description of biologically relevant processes may require rate equations that are too complex to solve using existing methods, hindering mechanistic insights into these processes. An example of significance is co-aggregation in environments containing multiple amyloid-beta (Abeta) peptide alloforms, which may play a crucial role in the biochemistry of Alzheimer's disease but whose mechanism is still poorly understood. Here, we use the mathematics of symmetry to derive a general integrated rate law valid for most plausible linear self-assembly reactions. We use it in conjunction with experimental data to determine the mechanism of co-aggregation of the most physiologically abundant Abeta alloforms: Abeta42, Abeta40, Abeta38 and Abeta37 peptides. We find that Abeta42 fibril surfaces catalyze the formation of co-oligomers, which accelerate new Abeta40, Abeta38 and Abeta37 fibril formation whilst inhibiting secondary nucleation of new Abeta42 fibrils. The simplicity, accuracy and broad applicability of our general integrated rate law will enable kinetic analysis of more complex filamentous self-assembly reactions, both with and without co-aggregation.