In research published in Science Advances, ALLOX scientists Mireia Seuma, André Faure and Ben Lehner used large-scale genomics and machine learning to study over 140,000 versions of a peptide called Aβ42, which forms harmful plaques in the brain and is known to play a central role in Alzheimer’s disease.

The team used massively parallel DNA synthesis to study how changing amino acids in Aβ affects the rate of amyloid nucleation – a critical step in the disease process – and genetically engineered yeast cells to measure this rate of reaction. They then used machine learning, a type of artificial intelligence, to analyse the results and generate a complete energy landscape of amyloid beta aggregation reaction, showing the effect of all possible mutations in this protein on how fast fibrils are formed.

The result was the first-ever large-scale map of how mutations shape the earliest events in protein aggregation, revealing that the hydrophobic core of Aβ42, at the C-terminus region of the protein, is structured at the transition state of the reaction. Indeed, a subset of residues in this region – known to form contacts in mature fibrils – are shown to have the strongest energetic couplings. The study provides a structural model for the initial steps of Aβ aggregation, which is key to understanding the onset of Alzheimer’s disease.  

“We measured the effect of more than 140,000 Aβ42 mutations and could apply neural networks, a type of machine learning, to extract, for each of them, the energy that drives the process of pathological aggregation. Mutations, and the interactions between them, made it possible for us to 'draw a portrait' of the transition state of the Aβ42 aggregation reaction. This is the key conformation driving the aggregation reaction, and it is extremely challenging (if not impossible) to study by classical biophysical methods” says Mireia Seuma, co-first author of the study together with Anna Arutyunyan, Postdoctoral Fellow at the Wellcome Sanger Institute.

“The approach we used in this study opens the door to revealing the structures of other protein transition states, including those implicated in other neurodegenerative diseases. The scale at which we analysed the amyloid peptides was unprecedented – it’s something that hasn’t been done before and we have shown it’s a powerful new method to take forward. We hope this takes us one step closer to developing treatments against Alzheimer’s disease and other neurodegenerative conditions.” says Professor Ben Lehner, Chief Scientific Advisor at ALLOX and dual affiliate between the CRG and the Wellcome Sanger Institute in the UK.

Mireia Seuma, Senior Scientist at ALLOX, has been awarded a three-year Torres Quevedo industrial research grant (PTQ2024-013687 awarded by MCIU/AEI/10.13039/501100011033) towards the scale-up and automation of the ALLOX experimental platform.

Read the Wellcome Sanger Institute News article

Read the research article

A complete energetic map of the Aβ42 nucleation reaction shows that mutations in the latter part of Aβ42 (C-terminus / hydrophobic core) are largely disruptive for nucleation. Credit: Anna Arutyunyan/Wellcome Sanger Institute