Inherent Adaptivity of Alzheimer Peptides to Crowded Environments

Abstract

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. The impact of crowding on the fibrillation pathways of Aβ40 and Aβ42, the most common peptide isoforms are studied. PEG and Ficoll are used as model crowders to mimic a macromolecular enriched surrounding. The fibrillar growth is monitored with the help of ThT‐fluorescence assays in order to extract two rates describing primary and secondary processes of nucleation and growth. Techniques as fluorescence correlation spectroscopy and analytical ultracentrifugation are used to discuss oligomeric states; fibril morphologies are 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, a vast variety of effects are found depending on the peptide, the crowder, or ionic strength of the solution. While investigations of the obtained rates with respect to a reactant‐occluded model are capable to display specific surface interactions with the crowder, the employment of crystallization‐like models reveal the crowder‐induced entropic gain with normalΔnormalΔGfibcrow=−116±210.28emk$\Delta \Delta G_{\text{fib}}^{\text{crow}}=-116\pm 21\; k$J mol−1 per volume fraction of the crowder.

The Prenucleation Equilibrium of the Parathyroid Hormone Determines the Critical Aggregation Concentration and Amyloid Fibril Nucleation

“…[23] We suppose that the considerably smaller lag-times for e. g. Aβ 40 indicate a slower oligomerization but a fast conversion rate which is possibly related to the toxicity of Aβ 40 oligomers. [65][66]…”