Researchers make breakthrough in Alzheimer’s disease drug development

An international team of researchers led by Lancaster University has made a promising breakthrough in the development of drugs to treat Alzheimer’s disease.

For the first time, scientists have developed a drug that works on both key aggregation-promoting ‘hotspots’ of the Tau protein in the brain – a key driver of neurodegeneration.

The drug, a peptide inhibitor called RI-AG03, was effective at preventing the buildup of Tau proteins in both laboratory and fruit fly studies.

The research, published in Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association, was led by Lancaster University in collaboration with the University of Southampton, Nottingham Trent University, Tokyo Metropolitan Institute of Medical Science and the University of Texas Southwestern Medical Center.

The Lancaster University team included the late Professor David Allsop and the late Dr Nigel Fullwood, both from the Faculty of Biomedical and Life Sciences at Lancaster University.

The article describes how RI-AG03 was first developed by Dr Aggidis in the late Professor Allsop’s laboratory, using computational biology, where it was tested in laboratory scales.

Lead author Dr. Anthony Aggidis, former postdoctoral research fellow at Lancaster University and visiting researcher at the University of Southampton, said: “Our research represents an important step towards creating treatments that can prevent the progression of diseases such as Alzheimer’s.

“By targeting both key areas of the Tau protein, this unique approach could help address the growing impact of dementia on society, and provide a much-needed new option for treating these devastating diseases.”

An important breakthrough

Tau proteins play a crucial role in maintaining the structure and function of neurons (brain cells). But in Alzheimer’s disease, these proteins malfunction, causing them to clump together and form long, winding fibrils.

As the fibrils build up, they create so-called neurofibrillary tangles: masses of twisted Tau proteins that clog the neurons, depriving them of the nutrients and signals they need to survive.

As more neurons die, memory, thinking and behavior become increasingly poor, leading to the cognitive decline seen in Alzheimer’s disease.

There are two specific ‘hotspots’ of the Tau protein where this clumping often occurs. While current treatments target one of these hotspots, RI-AG03 uniquely targets and blocks both.

Amritpal Mudher, professor of neuroscience at the University of Southampton, said: ‘There are two regions of the Tau protein that act as a zipper allowing it to aggregate. For the first time, we have a drug that is effective at inhibiting both. This dual-targeting mechanism is important because it addresses both domains that drive Tau aggregation, potentially paving the way for more effective treatments for neurodegenerative diseases such as Alzheimer’s.”

Targeted approach

The peptide-based approach is also more targeted than current treatments, potentially making it safer, with fewer side effects.

Dr. Aggidis said: ‘We know that the toxicity of the Tau protein is closely linked to its ability to aggregate, so by inhibiting aggregation we expect to see desired effects. But current anti-aggregation drugs have had many side effects because they can disrupt functions. Among many other proteins, RI-AG03 is designed specifically against the Tau protein, meaning it is less likely to interact undesirably with other proteins.”

Testing RI-AG03

To test its effectiveness in cells of a living organism, researchers at the University of Southampton then gave the drug to fruit flies that had pathogenic Tau. These fruit fly models of Alzheimer’s disease were generated by Dr Shreyasi Chatterjee, Senior Lecturer at Nottingham Trent University.

The researchers found that the drug suppressed neurodegeneration and extended the flies’ lifespan by about two weeks – a significant extension considering the insects’ lifespans.

To understand what was happening, the Southampton scientists looked deep into the brains of the fruit flies.

Professor Mudher said: ‘When we didn’t feed the flies the peptide inhibitor, they had a lot of pathogenic fibrils, which together formed a tangle. But when we fed them the drug, the pathogenic fibrils decreased significantly over time. quantity.”

“The higher the dosage, the greater the improvement we saw in the fruit fly’s lifespan.”

To make sure this wasn’t unique to fruit flies, researchers at the University of Texas Southwestern Medical Center tested the drug in a biosensor cell — a type of living human cell line designed to detect pathogenic tau fibril formation.

Here too, they found that the drug successfully entered cells and reduced the aggregation of Tau proteins.

The team believes their work will have a significant impact on drug development efforts in neurodegenerative diseases and now plans to test RI-AG03 in rodents before moving into clinical trials.

The research was funded by the Alzheimer’s Society UK.

Dr. Richard Oakley, Associate Director of Research and Innovation at the Society, said: “Dementia is the biggest cause of death in Britain, placing huge costs and pressures on our healthcare system. That’s why we’re committed to funding leading research like this. .

“This research takes promising steps toward a new unique therapy that targets Tau, a harmful protein in the brains of people with Alzheimer’s disease, preventing it from clumping together. This drug has the potential to be more targeted than others are currently being investigated and we hope this will result in fewer toxic side effects.

“It’s important to note that the research is still in its early stages, so we don’t know yet whether it will work or be safe for people, but it’s an exciting development and we look forward to seeing where it leads .

“Research will beat dementia, but we need to make this a reality sooner through more funding, more partnerships and more people participating in dementia research.”