Summary: Scientists have developed a drug that targets both major aggregation-promoting sites of the Tau protein, a key player in Alzheimer’s disease. This peptide inhibitor, RI-AG03, effectively prevents Tau buildup in lab studies and fruit flies, offering hope for new Alzheimer’s treatments.
Unlike current drugs, RI-AG03 uniquely blocks both Tau “hotspots,” potentially leading to safer, more targeted therapies. Researchers plan to test the drug in rodents before advancing to clinical trials.
Key Facts:
- RI-AG03 blocks Tau protein buildup, preventing neurodegeneration.
- It targets both major Tau “hotspots” for aggregation, a novel approach.
- The drug extended the lifespan of fruit fly models of Alzheimer’s disease.
Source: University of Southampton
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.
The research, published today [3 October 2024] in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, was undertaken by the University of Southampton in collaboration with Lancaster University, Nottingham Trent University, Tokyo Metropolitan Institute of Medical Science and UT Southwestern Medical Centre.
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.
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.
“It’s important to note that the study is in its early stages, so we don’t yet know if it will work or be safe for humans, but it’s an exciting development and we look forward to seeing where it leads.
“Research will beat dementia, but we need to make it a reality sooner through more funding, more partnerships, and more people taking part in dementia research. To find out about Alzheimer’s Society research or to take part visit alzheimers.org.uk/research.”
About this neuropharmacology and Alzheimer’s disease research news
Author: Steven Williams
Source: University of Southampton
Contact: Steven Williams – University of Southampton
Image: The image is credited to Neuroscience News
Original Research: Open access.
“A novel peptide-based tau aggregation inhibitor as a potential therapeutic for Alzheimer’s disease and other tauopathies” by Anthony Aggidis et al. Alzheimer’s & Dementia
Abstract
A novel peptide-based tau aggregation inhibitor as a potential therapeutic for Alzheimer’s disease and other tauopathies
INTRODUCTION
As aggregation underpins Tau toxicity, aggregation inhibitor peptides may have disease-modifying potential. They are therefore currently being designed and target either the 306VQIVYK311 aggregation-promoting hotspot found in all Tau isoforms or the 275VQIINK280 aggregation-promoting hotspot found in 4R isoforms. However, for any Tau aggregation inhibitor to potentially be clinically relevant for other tauopathies, it should target both hotspots to suppress aggregation of Tau isoforms, be stable, cross the blood-brain barrier, and rescue aggregation-dependent Tau phenotypes in vivo.
METHODS
We developed a retro-inverso, stable D-amino peptide, RI-AG03 [Ac-rrrrrrrrGpkyk(ac)iqvGr-NH2], based on the 306VQIVYK311 hotspots which exhibit these disease-relevant attributes.
RESULTS
Unlike other aggregation inhibitors, RI-AG03 effectively suppresses aggregation of multiple Tau species containing both hotspots in vitro and in vivo, is non-toxic, and suppresses aggregation-dependent neurodegenerative and behavioral phenotypes.
DISCUSSION
RI-AG03 therefore meets many clinically relevant requirements for an anti-aggregation Tau therapeutic and should be explored further for its disease-modifying potential for Tauopathies.
