Summary: Researchers have developed a drug that targets both main aggregation-promoting places of the Tau proteins, a key player in Alzheimer’s disease. This protein antagonist, RI-AG03, effectively prevents Tau formation in laboratory experiments and fruit fly, offering desire for new Alzheimer’s treatments.
Unlike recent drugs, RI-AG03 truly prevents both Tau “hotspots”, possibly leading to safer, more targeted solutions. Before moving forward with clinical trials, researchers intend to examine the medication on rodents.
Important Information:
- RI-AG03 stones Tau proteins buildup, preventing degeneration.
- It targets both main Tau “hotspots” for formation, a fascinating technique.
- The medicine extended the duration of fruit fly types of Alzheimer’s disease.
Origin: University of Southampton
A global team of researchers has made a significant advance in the development of drugs to treat Alzheimer’s Disease.
For the first time, researchers have created a substance that targets both significant aggregation-promoting “hotspots” of the Tau protein, filling a crucial gap in existing treatments.
In both laboratory and berries fly studies, the peptide inhibitor RI-AG03 was successful in halting the accumulation of Tau proteins, a key driver of neurodegeneration.
The study, published today]3 , October 2024] in , Alzheimer’s &, Dementia: The Journal of the Alzheimer’s Association,  , was undertaken by the University of Southampton in partnership with Lancaster University, Nottingham Trent University, Tokyo Metropolitan Institute of Medical Science and UT Southwestern Medical Centre.
Dr. Anthony Aggidis, a visiting researcher at the University of Southampton and former doctoral research connect at Lancaster University, the lead author of the study, said:” Our study represents a significant step toward developing solutions that can stop the spread of diseases like Alzheimer’s disease.
This distinctive approach may help address the growing impact of memory on society by targeting both of the crucial locations on the Tau proteins, giving a desperately needed new option for treating these catastrophic diseases.
A major breakthrough
Tau proteins are essential for maintaining the structure and function of neurons ( brain cells ). But in Alzheimer’s disease, these molecules damage, clumping together to shape long, twisting particles.
As the particles grow, they form what are known as neurofibrillary strands, or masses of contorted Tau proteins that clog the cells, preventing them from receiving the nutrition and signals they need to succeed.
As more cells die, memory, thinking, and behaviour become exceedingly impaired, leading to the mental reduction seen in Alzheimer’s.
This blending occurs in two distinct “hotspots” of the Tau proteins. While existing treatments specific one or the other of these areas, RI-AG03 truly priorities and prevents both.
One of the lead writers on the report, Amritpal Mudher, Professor of Neuroscience at the University of Southampton, claims that there are two parts of the Tau proteins that act like a jacket and help its index.
We have a drug that, for the first time, successfully blocks both of these parts. This dual-targeting strategy is important because it addresses both the Tau formation domain, potentially enabling the development of more potent therapies for degenerative disorders like Alzheimer’s.
Targeted view
The peptide-based technique is also more targeted than existing solutions, possibly making it safer, with fewer side effects.
We are aware that the Tau protein’s toxicity is directly related to its capacity to aggregate, but by preventing aggregation we can anticipate appealing effects, says Dr. Aggidis.
However, the recent formation antagonists have a number of negative effects, as they can impair the functionality of many other protein.
” RI-AG03 is specifically designed against the Tau protein, meaning it’s less likely to undesirably interact with other proteins”.
Testing RI-AG03
The report describes how RI-AG03 was initially developed by Dr Aggidis, in the experiment of the overdue Prof David Allsop, using mathematical biology at Lancaster University, where it was tested in laboratory food.
Researchers at the University of Southampton administered the drug to fruit flies that had pathogenic Tau in order to test its potency in living cells. Dr. Shreyasi Chatterjee, a senior lecturer at Nottingham Trent University, created these fruit-fly Alzheimer’s disease models.
The researchers discovered that the medication reduced neurodegeneration and extended the life of the flies by about two weeks, a significant improvement given the length of the insects ‘ lives.
To understand what was happening, Southampton’s scientists looked deep into the brains of the fruit flies.
Prof Mudher said:” When we did n’t feed the flies with the peptide inhibitor, they had lots of the pathogenic fibrils, which group together to make up a tangle. However, the number of pathogenic fibrils significantly decreased when we gave them the medicine.
” The higher the dosage given, the greater the improvement we saw in the fruit fly’s lifespan”.
Researchers at UT Southwestern Medical Center tested the drug in a biosensor cell, a type of living human cell line that has been developed to detect pathogenic tau fibril formation, to make sure this was n’t specific to fruit flies.
They discovered that the drug successfully penetrated the cells and stopped the Tau protein aggregation.
The team now intends to test RI-AG03 in rodents before moving on to clinical trials because they believe their work will have a significant impact on drug discovery efforts in the field of neurodegenerative diseases.
The research was funded by the Alzheimer’s Society. Dr. Richard Oakley, Associate Director of Research and Innovation, stated that dementia is the UK’s biggest killer and that it places a lot of pressure on the healthcare system. This is why we are committed to funding cutting-edge studies like this.  ,
This study makes some promising progress toward a novel, one-of-a-kind treatment that blocks the clumping of Tau, a harmful protein found in people with Alzheimer’s, from Alzheimer’s patients. We hope this drug will have fewer toxic side effects because it has the potential to be more targeted than other drugs being studied right now.  ,
We do n’t yet know whether the study will work or be safe for people, but it’s an exciting development and we look forward to seeing where it leads. It’s important to note that the study is in its early stages.  ,
” 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.
Anthony Aggidis and al.,” A novel peptide-based tau aggregation inhibitor as a potential therapeutic for Alzheimer’s disease and other tauopathies.” 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
Therefore, RI-AG03 meets a number of clinically relevant requirements for a Tau therapeutic that blocks aggregation, and its potential to treat Tauopathies may be improved.
