An international team of researchers have 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 major aggregation-promoting ‘hotspots’ of the
Tau protein - addressing a critical gap in current treatments.
The drug, a peptide inhibitor called RI-AG03, was effective at preventing the build-up of Tau proteins - a key driver of neurodegeneration - in both lab and fruit fly studies.
Dr Anthony Aggidis, lead author of the paper, Visiting Researcher at the
University of Southampton and former Postdoctoral Research Associate at Lancaster University said: “Our research represents an important step toward creating treatments that can prevent the progression of diseases like
Alzheimer’s disease.
By targeting both of the key areas on the Tau protein, this unique approach could help address the growing impact of
dementia on society, providing a much-needed new option for treating these devastating diseases.”
A significant 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, clumping together to form long, twisting fibrils.
As the fibrils accumulate, they create what are called neurofibrillary tangles - masses of twisted Tau proteins that clog the neurons, preventing them from getting the nutrients and signals they need to survive.
As more neurons die, memory, thinking, and behaviour become increasingly impaired, leading to the cognitive decline seen in
Alzheimer’s.
There are two specific ‘hotspots’ of the Tau protein where this clumping tends to happen. While current treatments target one or the other of these hotspots, RI-AG03 uniquely targets and blocks both.
There are two regions of the Tau protein that act like a zipper to enable it to aggregate, says Amritpal Mudher , Professor of Neuroscience at the
University of Southampton and one of the lead authors on the paper.
For the first time, we have a drug which is effective in inhibiting both these regions. This dual-targeting mechanism is significant because it addresses both domains that stimulate Tau aggregation, potentially paving the way for more effective treatments for
neurodegenerative diseases like
Alzheimer’s.
Targeted approach
The peptide-based approach is also more targeted than current treatments, potentially making it safer, with fewer side effects.
We know that the toxicity of the Tau protein is intimately linked with its ability to aggregate, so by inhibiting aggregation we expect to see desirable effects, says Dr Aggidis.
But current aggregation inhibitors have had many side effects because they can interfere with the functions of many other proteins.
RI-AG03 is specifically designed against the Tau protein, meaning it’s less likely to undesirably interact with other proteins
Testing RI-AG03
The paper describes how RI-AG03 was first developed by Dr Aggidis, in the laboratory of the late Prof David Allsop, using computational biology at Lancaster University, where it was tested in lab dishes.
Scientists used a special imaging technique to observe how Tau protein clumps in the brain tissue of genetically modified flies in response to treatment with RI-AG03. Without the treatment (A), they saw toxic clumps of Tau fibrils (arrow) and oligomers (arrowhead). After treatment (B), those harmful clumps disappeared, and only large round structures remained, which the scientists believe are less harmful.
Scientists used a special imaging technique to observe how Tau protein clumps in the brain tissue of genetically modified flies in response to treatment with RI-AG03. Without the treatment (A), they saw toxic clumps of Tau fibrils (arrow) and oligomers (arrowhead). After treatment (B), those harmful clumps disappeared, and only large round structures remained, which the scientists believe are less harmful. To test its effectiveness in cells within 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 who is a Senior Lecturer at Nottingham Trent University.
The researchers found the drug suppressed neurodegeneration and extended the lives of the flies by around two weeks – a significant extension considering the life span of the insects.
To understand what was happening, Southampton’s scientists looked deep into the brains of the fruit flies.
Prof Mudher said: When we didn’t feed the flies with the peptide inhibitor, they had lots of the pathogenic fibrils, which group together to make up a tangle. But when we fed them with the drug, the pathogenic fibrils decreased significantly in quantity.”
The higher the dosage given, the greater the improvement we saw in the fruit fly’s lifespan.
To make sure this wasn’t unique to fruit flies, researchers at UT Southwestern Medical Centre tested the drug in a biosensor cell - a type of living human cell line that is engineered to detect pathogenic tau fibril formation.
Here too, they found the drug successfully penetrated the cells and reduced the aggregation of Tau proteins.
The team believe their work will have a significant impact on drug discovery efforts in the field of
neurodegenerative diseases and now plans to test RI-AG03 in rodents, before proceeding to clinical trials.
The research was funded by the
Alzheimer’s Society . Dr Richard Oakley, Associate Director of Research and Innovation, said: Dementia is the UK’s biggest killer, and it applies enormous cost and pressure to our healthcare system which is why we’re committed to funding world leading studies like this one.
This research is taking promising steps towards a new one-of-a-kind therapy which targets Tau, a damaging protein in the brains of people living with
Alzheimer’s, preventing it from clumping together. This drug has the potential to be more targeted than others currently being studied, and we hope it will result in fewer toxic side effects.