New large-scale study maps early triggers of Alzheimer’s protein aggregation

A new large -scale study has mapped the first molecular events that control the formation of harmful amyloid proteinaggregates in Alzheimer’s disease, pointing to a new potential therapeutic target.

Published today (June 11) in Science is progressingResearchers of the Wellcomen Sanger Institute, Center of Genomic Regulation (CRG) and Institute for Bio-engineering of Catalonia (IBEC) used large-scale genomics and mechanical learning to study more than 140,000 versions of a peptide called Aβ42 and a central plaques in the brain.

This research is an important step to help scientists find new ways to prevent Alzheimer’s disease, and the methods used in the study can be applied to other protein reactions.

More than 55 million people are hit worldwide by dementia and it is estimated that 60 to 70 percent of these cases are Alzheimer’s disease. Most current treatments for Alzheimer’s slow or stop the disease, but help manage the symptoms.

Amyloid beta (AP) is a peptide – a short chain of amino acids. Amyloid beta peptides tend to clump and aggregate, which means that elongated structures are known as amyloid fibrillen. Over time, these fibrils gather in plaques that are the pathological characteristics of more than 50 neurodegenerative diseases, and in particular play a critical central role in Alzheimer’s disease.

For freely flowing AP peptides to convert into stable, structured fibrillen, they require a certain amount of energy. The intervening, short-term condition just before the peptides begin to form a fibril, is known as the ‘transition state’ it is extremely unlikely that it is in most people.

Understanding these structures and reactions is essential for the development of therapies that can treat and prevent neurodegenerative diseases. However, it is very difficult to study short -term transition states with high energy with the help of classic methods. As such, understanding how AP starts to aggregate continues to a major challenge in the research of Alzheimer’s.

That is why researchers of this new study of the Sanger Institute, Center of Genomic Regulation and the Institute of Bio -engineering of Catalonia tried to understand how to change the genetics of AP influence the speed of the aggregation action. In particular, the researchers looked at Aβ42 – a type AP -Peptide with 42 amino acids that are often found at those with Alzheimer’s.

The researchers used a combination of three techniques to be able to handle large amounts of information about Aβ42 at the same time. The team used massive parallel DNA synthesis to study how changing amino acids in AP influence the amount of energy needed to form fibril, and genetically modified yeast cells to measure this reaction speed. They then used machine learning, a kind of artificial intelligence, to analyze the results and to generate a complete energy landscape of amyloid beta aggregation reaction, which shows the effect of all possible mutations in this protein on how quickly fibrilles are formed.

With these techniques, the researchers were able to conduct the study on a large scale and at the same time view more than 140,000 versions of Aβ42. This scale has never been achieved before and helps improve the quality and accuracy of the models developed in the study.

The researchers discovered that only a few important interactions between specific parts of the amyloid protein had a strong influence on the speed of fibril formation. They found that the Aβ42 aggregation reaction starts at the end of the protein, known as the C-terminal area, one of the hydrophobic cores of the protein-the tightly packed water-repellent area of ​​the peptide. As it is where the peptide starts to aggregate in fibril, the researchers suggest that it is the interactions in the C-terminal area that should be prevented from protecting and treating Alzheimer’s disease.

This is the first large -scale map of how mutations influence the behavior of a protein in the notoriously difficult to study the transition state. By identifying the interactions that stimulate the formation of amyloid fibrils, the team believes that the prevention of the formation of this transition status could pave the way for new therapeutic strategies, so that hope for future treatments of Alzheimer’s can be offered. In addition, the researchers emphasize the broad usability of their method and they note that it has potential to be used in various proteins and diseases in future studies.

By measuring the effects of more than 140,000 different versions of proteins, we have made the first extensive card of how individual mutations change the energy landscape of amyloid beta -aggregation – a process that is central to the development of Alzheimer’s disease. Our data -driven model offers the first display with high resolution of the transition state of the reaction, so that the door is opened for more targeted strategies for therapeutic intervention. “

Dr. Anna Arutyunyan, co-first author and postdoctoral fellow, Wellcare Sanger Institute

Dr. Benedetta Bolognesi, co-senior author and group leader at the Institute for Bio-engineering of Catalonia, said: “Our study is new for two reasons: firstly, our method” Kinetic selection “Method how fast reactions occur and does this for thousands of reactions in parallel of the work of the work of the work of the work of the work of the work of the work of the work of the work of the work of the work of the work, the work-of-the-hikes, work-based Interactions of the interactions, we can initiate mutations of the interaction.

Dr. Richard Oakley, Associate Director of Research and Innovation at Alzheimer’s Society, said: “Dementia is the biggest problem of health and social care of our time and about a million people in the UK living with this devastating state. This study makes the power of technology to be tested in the Klinische Supply. 130 Medicines. Urgent need to develop more effective and safer treatments, research like that is of crucial importance to continue to increase our understanding of the very complex processes involved in Alzheimer’s disease.

Professor Ben Lehner, co-senior author, head of generative and synthetic genomics at the Wellcare Sanger Institute and Icrea Research Professor at the Center for Genomic Regulation (CRG), said: “The approach that we have used in this study opens the door to reveal the structures of other protein, including the protein-wit, Non-analyzed The amyloid peptides that were not analyzed, the amyloid peptides that have analyzed the amyloid peptides that have analyzed the amyloid peptides of the amyloid peptides. Is something that has never been done before and we have shown that it is a powerful new method to continue.