Inherent adaptivity of Alzheimer peptides to crowded environments

Abstract

Amyloid𝜷(A𝜷) is the major constituent in senile plaques of Alzheimer’sdisease in which peptides initially undergo structural conversions to formelongated fibrils. The impact of crowding on the fibrillation pathways of A𝜷40and A𝜷42, the most common peptide isoforms are studied. PEG and Ficoll areused as model crowders to mimic a macromolecular enriched surrounding.The fibrillar growth is monitored with the help of ThT-fluorescence assays inorder to extract two rates describing primary and secondary processes ofnucleation and growth. Techniques as fluorescence correlation spectroscopyand analytical ultracentrifugation are used to discuss oligomeric states; fibrilmorphologies are investigated using negative-staining transmission electronmicroscopy. While excluded volume effects imposed by macromolecularcrowding are expected to always increase rates of intermolecular interactionsand structural conversion, a vast variety of effects are found depending on thepeptide, the crowder, or ionic strength of the solution. While investigations ofthe obtained rates with respect to a reactant-occluded model are capable todisplay specific surface interactions with the crowder, the employment ofcrystallization-like models reveal the crowder-induced entropic gain with𝚫𝚫Gcrowfib=−116±21kJmol−1per volume fraction of the crowder.