Oxidative Stress Impacts Peptide Aggregation

A recent study published in Chemical Science shed new light on how cell membranes can impact the peptide structure and aggregation. The team used both laboratory experiments and computer simulations to examine peptide aggregation in model systems, ultimately discovering that membrane composition plays a crucial role in peptide aggregation. The effects differ depending on the peptide’s properties, including its charge and attraction to the membrane.

One of the peptides studied, Aβ40, which is associated with Alzheimer’s disease, aggregated faster in the presence of all membranes. However, the aggregation of another peptide, uperin 3.5, was prevented entirely in the presence of the same amount of oxidized membranes.

The study’s lead author, Dr. Torsten John, explains, “One of the effects of stress in the body is that it leads to oxidative processes and thus changes the chemical composition of membranes. In our experiments, we compared the effects of oxidized membranes with those that were not changed.”

The authors deliberately chose peptides that aggregate similarly but have a different origin – Aβ40 is known to be deposited in the brains of people with Alzheimer’s disease, while uperin 3.5 is an antimicrobial peptide first discovered in an Australian toad species. The study further discussed the functional role of amyloid peptides and their links to both neurodegenerative diseases and antimicrobial properties.

The researchers used molecular dynamics simulations and experiments to explore the influence of zwitterionic (POPC), anionic (POPG) and oxidized (PazePC) phospholipids, as well as cholesterol, and mixtures thereof, on the self-assembly kinetics of the Aβ40 peptide and the uperin 3.5 peptide.

They proposed a model that explains how changes in peptide-membrane binding, electrostatics, and peptide secondary structure stabilization determine the nature of peptide self-assembly. They found that electrostatic interactions are a primary driving force for peptide-membrane interaction, enabling them to propose a model for predicting how cellular changes might impact peptide self-assembly in vivo.

Peptide fibrils have been implicated in aging-related and neurodegenerative diseases, such as Alzheimer’s, but have also been identified as functional, non-pathological states that have developed structural advantages as functional materials. The researchers suggest that their study could help to predict how cellular changes might impact peptide self-assembly in vivo, potentially leading to new therapies for neurodegenerative diseases.