Inherent Adaptivity of Alzheimer Peptides to Crowded Environments.

Amyloid β (Aβ) is the major constituent in senile plaques of Alzheimer's disease in which peptides initially undergo structural conversions to form elongated fibrils. We study the impact of crowding on the fibrillation pathways of Aβ 40 and Aβ 42 , the most common peptide isoforms. We use PEG and Ficoll as model crowders to mimic a macromolecular enriched surrounding. The fibrillar growth was monitored with the help of ThT-fluorescence assays in order to extract two rates describing primary and secondary processes of nucleation and growth. We used techniques as fluorescence correlation spectroscopy and analytical ultracentrifugation to discuss oligomeric states; fibril morphologies were investigated using negative-staining transmission electron microscopy. While excluded volume effects imposed by macromolecular crowding are expected to always increase rates of intermolecular interactions and structural conversion, we found a vast variety of effects depending on the peptide, the crowder or ionic strength of the solution. Final investigations of the obtained rates with respect to a reactant-occluded model revealed specific surface interactions with the crowder. Moreover, we could employ crystallisation-like models to also extract the crowder-induced entropic gain with ΔΔG fib crow =-116±21 kJ mol -1 per volume fraction of the crowder. This article is protected by copyright. All rights reserved.