Researchers make breakthrough in developing drugs against Alzheimer's disease

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 targets 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 in preventing the formation of tau proteins in both laboratory and fruit fly studies.

The study, 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 was developed using computational biology in the late Professor Allsop's laboratory, where it was tested in laboratory dishes.

The main author Dr. Anthony Aggidis, a former postdoctoral researcher at Lancaster University and visiting researcher at the University of Southampton, said: “Our research represents an important step towards developing treatments that can prevent the progression of diseases such as Alzheimer's disease.”

“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 to treat these devastating diseases.”

A significant breakthrough

Tau proteins play a crucial role in maintaining the structure and function of neurons (brain cells). However, in Alzheimer's disease, these proteins fail and clump together into long, winding fibrils.

When the fibrils accumulate, they form so-called neurofibrillary tangles – masses of twisted tau proteins that clog neurons and prevent them from receiving the nutrients and signals they need to survive.

As more neurons die, memory, thinking, and behavior become more impaired, 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 or other of these hotspots, RI-AG03 exclusively targets and blocks both.

Amritpal Mudher, professor of neuroscience at the University of Southampton, said: “There are two regions of the tau protein that function like a zipper to enable aggregation. For the first time, we have a drug that effectively inhibits both.” This dual-targeting mechanism is significant because it targets both domains that stimulate 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 and with fewer side effects.

Dr. Aggidis said: “We know that the toxicity of the tau protein is closely related to its ability to aggregate, so we expect desirable effects by inhibiting aggregation. However, current aggregation inhibitors have had many side effects because they can impair functions.” “RI-AG03 is specifically designed against the tau protein compared to many other proteins, meaning it is less likely to interact with other proteins.”

Testing RI-AG03

To test its effectiveness in cells of a living organism, researchers at the University of Southampton then administered the drug to fruit flies that had pathogenic tau. These fruit fly models of Alzheimer's disease were developed by Dr. Shreyasi Chatterjee, a lecturer at Nottingham Trent University.

The researchers found that the drug suppressed neurodegeneration and extended the flies' lives by about two weeks – a significant increase considering the insects' lifespan.

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 lots of pathogenic fibrils grouped together in a ball. But when we fed them the drug, the pathogenic fibrils decreased significantly in quantity.”

“The higher the dosage administered, the greater the improvement in the lifespan of the fruit fly.”

To make sure this wasn't just happening in 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 the formation of pathogenic tau fibrils.

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

The team expects their work to have a significant impact on drug discovery in neurodegenerative diseases and now plans to test RI-AG03 in rodents before moving on to clinical trials.

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

Dr. Richard Oakley, the society's deputy director of research and innovation, said: “Dementia is the leading cause of death in the UK and creates huge costs and pressures on our healthcare system. That’s why we’re committed to funding world-leading studies like this one.”

“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, and prevents it from clumping together. This drug has the potential to be more targeted than others currently being studied and we hope this will result in fewer toxic side effects.

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

“Research will defeat dementia, but we need to make it a reality faster, with more funding, more partnerships and more people involved in dementia research.”