Sticker-and-Linker Model for Amyloid BetaCondensation and Fibrillation

Abstract

A major pathogenic hallmark of Alzheimers disease is the presence of neurotoxic plaques composed of amyloid beta (A{beta}) peptides in patients brains. The pathway of plaque formation remains elusive, though some clues appear to lie in the dominant presence of A{beta}1-42 in these plaques despite A{beta}1-4 making up approximately 90% of the A{beta} pool. We hypothesise that this asymmetry is driven by the hydrophobicity of the two extra amino acids that are incorporated in A{beta}1-42. To investigate this hypothesis at the level of single molecules, we have developed a molecular sticker-and-linker lattice model of unfolded A{beta}. The model protein has a single sticker that may reversibly dimerise and elongate into semi-flexible linear oligomers. The growth is hampered by excluded-volume interactions that are encoded by the hydrophilic linkers but is rendered cooperative by the attractive interactions of hydrophobic linkers. For sufficiently strong hydrophobicity, the chains undergo liquid-liquid phase-separation (LLPS) into condensates that facilitate the nucleation of fibres. We find that a small fraction of A{beta}1-40 in a mixture of A{beta}1-40 and A{beta}1-42 shifts the critical concentration for LLPS to lower values. This study provides theoretical support for the hypothesis that LLPS condensates act as a precursors for aggregation and provides an explanation for the A{beta}1-42-enrichment of aggregates in terms of hydrophobic interactions.