‘Unprecedented’ large-scale study involving Wellcome Sanger Institute unearths first steps in how amyloid plaques form in Alzheimer’s

A complex study of unprecedented scale using pioneering techniques has been described as a significant step forward in the effort to find new ways to prevent Alzheimer’s disease.

Wellcome Sanger Institute researchers and their collaborators have mapped, for the first time, the initial molecular events that drive the formation of harmful amyloid protein aggregates in the disease.

Identifying these interactions could help pave the way for much-needed new therapeutic strategies.

It is believed that more than 55 million people worldwide are impacted by dementia and that about 60 to 70 per cent of them have Alzheimer’s. Most current treatments do not slow or stop the disease, but only help to manage its symptoms.

Harmful plaques in the brain play a critical role in Alzheimer’s and, indeed, are a pathological hallmark of more than 50 neurodegenerative diseases.

They form because amyloid beta (Aβ) peptides - short chains of amino acids - have a tendency to clump and aggregate, forming elongated structures known as amyloid fibrils. These fibrils accumulate over time into plaques.

We know that for free-flowing Aβ peptides to convert into stable structured fibrils, a certain amount of energy is required.

There is an intermediate, short-lived state just before the peptides begin to form a fibril that is known as the ‘transition state’. It is extremely unlikely to form, which is why fibrils never develop in most people.

Understanding these structures and reactions is vital to help treat and prevent neurodegenerative disease but the short-lived high transition states are extremely difficult to study using classical methods.

It means that understanding how Aβ starts aggregating has proved a major challenge in Alzheimer’s research.

For the new study, published in Science Advances, large-scale genomics and machine learning were used to study more than 140,000 versions of a peptide called Aβ42 - one with 42 amino acids - that forms these plaques and is commonly found in Alzheimer’s.

The researchers from the Wellcome Sanger Institute, Centre of Genomic Regulation (CRG) and Institute for Bioengineering of Catalonia (IBEC) sought to understand how changing the genetics of Aβ affected the rate of the aggregation reaction.

Three techniques were combined to handle large amounts of data about Aβ42.

Massively parallel DNA synthesis was used to study how changing amino acids in Aβ affects the amount of energy needed to form a fibril.

Genetically engineered yeast cells were used to measure this rate of reaction.

Machine learning, a type of artificial intelligence, was then deployed to analyse the results and generate a complete energy landscape of amyloid beta aggregation reaction. This showed the effect of all possible mutations in this protein on how fast fibrils are formed.

Using these methods enabled the researchers to look at more than 140,000 versions of Aβ42 simultaneously - a scale which has not been achieved before but helps improve the quality and accuracy of the models developed.

They found only a few key interactions between specific parts of the amyloid protein had a strong influence on the speed of fibril formation.

The Aβ42 aggregation reaction begins at the end of the protein, known as the C-terminal region. This is one of the hydrophobic cores of the protein – a tightly-packed water-repellent region.

The researchers believe interactions in this C-terminal region need to be prevented to protect against and treat Alzheimer’s disease.

Dr Anna Arutyunyan, co-first author and postdoctoral fellow at the Wellcome Sanger Institute, said: “By measuring the effects of over 140,000 different versions of proteins, we have created the first comprehensive map of how individual mutations alter the energy landscape of amyloid beta aggregation – a process central to the development of Alzheimer’s disease. Our data-driven model offers the first high-resolution view of the reaction’s transition state, opening the door to more targeted strategies for therapeutic intervention."

The method could also be used across a range of proteins and diseases.

Dr Benedetta Bolognesi, co-senior author and Group Leader at the Institute for Bioengineering of Catalonia, added: “Our study is novel for two reasons: Firstly, our ‘kinetic-selection’ method measures how fast reactions occur — and it does so for thousands of reactions in parallel, capturing the true rate-limiting steps of the aggregation reaction. “Secondly, by combining mutations, we can systematically probe the interactions between different parts of the protein as the aggregation reaction initiates. This is crucial to understand the first events in the process of protein aggregation that leads to dementia, but it also offers a powerful framework to dissect the key initiating steps of many biological reactions, not just those we’ve studied so far. I look forward to seeing all the ways in which this strategy will be employed in the future."

Dr Richard Oakley, associate director of research and innovation at Alzheimer’s Society, said: “Dementia is the biggest health and social care issue of our time and around one million people in the UK are living with this devastating condition. This study harnesses the power of technology to fill a key piece of the puzzle in how toxic amyloid proteins accumulate in the brain and improves our understanding of how genetics influences the way this protein forms plaques.

“With more than 130 drugs currently being tested in Alzheimer’s disease clinical trials and an urgent need to develop more effective and safer treatments, research like this is critical to continue growing our understanding of the highly complex processes involved in Alzheimer’s disease. Our Forget Me Not Appeal runs through June, and we’re encouraging people to help fund life-changing research by donating at alzheimers.org.uk/forgetmenotappeal.”

Professor Ben Lehner, co-senior author, head of generative and synthetic genomics at the Wellcome Sanger Institute and ICREA research professor at the CRG, said: “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.”