New Research Approach to the Development of Alzheimer’s
Correlation of oxidative stress on peptide aggregation investigated
Despite many advances in research, there is as yet no cure for many diseases of old age such as Alzheimer’s dementia. A new hypothesis for the development of Alzheimer’s is the aggregation of peptides, i.e. their “clumping”, in the brains of sufferers. But stress has also been suspected as a possible trigger.
Scientists from the University of Leipzig, the Australian Monash University, the Leibniz Institute for Surface Modification (IOM) and the Georg August University of Göttingen have investigated the connections between oxidised cell membranes and peptide aggregation and published the research results in the journal “Chemical Science”.
Stress alters the chemical composition of cell membranes.
With their study, the researchers wanted to better understand how cell membranes in the body influence the structure of peptides – these are molecules made up of amino acids – and their aggregation. To do this, they used model systems that they can control well experimentally. First author Dr. Torsten John, who did his doctorate under the supervision of Prof. Dr. Bernd Abel in Leipzig and is now researching at the Massachusetts Institute of Technology (MIT) in the USA, explains: “Stress leads to oxidative processes in the body, among other things, and thus changes the chemical composition of membranes. In our experiments, we compared the effects of oxidised membranes with those that were not altered”.
The scientists combined both biophysical laboratory experiments and computer simulations to better understand peptide aggregation. “Computer simulations, known as molecular dynamics simulations, provide molecular insights into the mechanisms of interactions between membranes and peptides,” says Prof. Abel.
It was already known that membrane composition plays an important role in the aggregation of peptides. But the role of oxidised membranes has been little studied so far. The researchers found that the effects differ between the peptides. One of the peptides studied (Aβ40), which is associated with Alzheimer’s disease, aggregated faster in the presence of all membranes. In contrast, the aggregation of another peptide (uperin 3.5) was completely prevented in the presence of the same amount of oxidised membranes. Prof. Abel explains: “Depending on the property of the peptide, including its charge, its attraction to the membrane changes, and thus the strength of its influence. If the peptides accumulate on the membrane surface, this accelerates their assembly and aggregation. However, if the attraction is very strong and they change their structure into a helix, then they can no longer aggregate.”
Possible links between peptide aggregation in neurodegenerative diseases
The scientists:inside deliberately chose peptides for their study that aggregate similarly but have a different origin. Aβ40 is known to be deposited in the brains of people with Alzheimer’s disease, whereas uperin 3.5 is an antimicrobial peptide first discovered in an Australian toad species. The researchers led by cooperation partner Prof. Dr. Lisandra L. Martin from the Australian Monash University had already reported on possible connections between the aggregation of peptides in neurodegenerative diseases and the antimicrobial property of the peptides.
The study, published in the journal Chemical Science, further discusses the functional role of amyloid peptides. The research took place within the DFG Collaborative Research Centre SFB TRR 102 “Polymers under constraint: constrained and controlled molecular order and mobility”.
Torsten John et al; Lipid oxidation controls peptide self-assembly near membranes through a surface attraction mechanism; Chem. Sci., 2023, Advance Article