An international group of researchers from Lancaster University has recently achieved a significant milestone in creating new medications for Alzheimer’s Disease.
For the very first time, scientists have introduced a drug that addresses two key aggregation-prone ‘hotspots’ of the Tau protein in the brain, which plays a major role in neurodegeneration.
This drug, named RI-AG03 and classified as a peptide inhibitor, has shown promise in thwarting the accumulation of Tau proteins in studies conducted in the lab and on fruit flies.
The findings, detailed in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, were the result of collaboration among Lancaster University, the University of Southampton, Nottingham Trent University, Tokyo Metropolitan Institute of Medical Science, and the University of Texas Southwestern Medical Centre.
The research team from Lancaster included the late Professor David Allsop and the late Dr. Nigel Fullwood, both affiliated with the Faculty of Biomedical and Life Sciences.
The paper emphasizes how RI-AG03 was initially designed by Dr. Aggidis in Professor Allsop’s lab, utilizing computational biology methods for testing in laboratory dishes.
Lead author Dr. Anthony Aggidis, a former Postdoctoral Research Associate at Lancaster University and visiting researcher at the University of Southampton, remarked: “Our research marks a crucial advancement towards developing treatments that can halt the progression of diseases such as Alzheimer’s.”
“By focusing on both significant regions of the Tau protein, this innovative approach could help mitigate the rising effects of dementia on society, offering a much-anticipated new treatment option for these life-altering diseases.”
A major advancement
Tau proteins are vital for maintaining neuron structure and function. However, in Alzheimer’s disease, these proteins misbehave, clumping together into long, twisting threads.
Accumulation of these threads leads to neurofibrillary tangles—dense clusters of twisted Tau proteins that obstruct neurons, hindering their ability to receive essential nutrients and signals.
As more neurons perish, memory, cognitive functions, and behavior deteriorate, resulting in the cognitive decline associated with Alzheimer’s.
There are two particular ‘hotspots’ on the Tau protein where this clumping typically occurs. While existing treatments target one of these hotspots at a time, RI-AG03 uniquely targets both simultaneously.
Professor Amritpal Mudher of the University of Southampton shared: “There are two regions on the Tau protein that function like a zipper, facilitating its aggregation. For the first time, we have a drug that effectively inhibits both regions. This dual-targeting strategy is groundbreaking as it tackles both areas that promote Tau aggregation, potentially leading to improved treatments for neurodegenerative disorders like Alzheimer’s.”
A focused strategy
This peptide-based method is also more precise than existing treatments, possibly enhancing safety and reducing side effects.
Dr. Aggidis stated: “We understand that the Tau protein’s toxicity is closely tied to its aggregation capacity, so by inhibiting this process, we anticipate positive results. However, current aggregation blockers have shown numerous side effects due to their interference with other protein functions. RI-AG03 has been specifically designed to target the Tau protein, making unintended interactions with other proteins less likely.”
Evaluating RI-AG03
To assess its effectiveness in live cells, researchers at the University of Southampton administered the drug to fruit flies displaying pathogenic Tau. These fruit fly models of Alzheimer’s were created by Dr. Shreyasi Chatterjee, a Senior Lecturer at Nottingham Trent University.
The researchers observed that the drug reduced neurodegeneration and extended the fruit flies’ lifespan by approximately two weeks—a significant increase considering the insects’ short life expectancy.
To determine the underlying processes, Southampton scientists delved into the brains of the fruit flies.
Professor Mudher noted: “When the flies were not provided with the peptide inhibitor, they exhibited a high number of pathogenic fibrils that contribute to tangle formation. However, upon administering the drug, the quantity of these fibrils dropped significantly.”
“We observed that the higher the dose given, the more we noticed improvements in the fruit flies’ longevity.”
To confirm that this effect wasn’t exclusive to fruit flies, researchers at the University of Texas Southwestern Medical Centre tested the drug on a biosensor cell, which is a type of engineered human cell line designed to detect the formation of pathogenic tau fibrils.
In this case as well, they found that the drug successfully entered the cells and mitigated Tau protein aggregation.
The team is optimistic that their research will greatly influence drug development in the field of neurodegenerative diseases and plans to advance RI-AG03 testing in rodents before initiating clinical trials.
This research received funding from the Alzheimer’s Society UK.
Dr. Richard Oakley, Associate Director of Research and Innovation at the Society, commented: “Dementia is the UK’s leading cause of death and poses immense financial and operational challenges for our healthcare system, which is why we are dedicated to funding exceptional studies like this one.
“This research is taking groundbreaking strides toward a unique therapy that targets Tau, a harmful protein affecting the brains of individuals with Alzheimer’s, preventing its aggregation. This drug could offer more targeted treatment than currently studied alternatives, and we are hopeful it will lead to fewer toxic side effects.
“It’s important to recognize that this study is still in its early phases; therefore, we do not yet know if it will be effective or safe for humans. Nonetheless, it is an exhilarating development, and we are eager to see its future progression.
“Research will triumph over dementia, but we must expedite this reality through increased funding, greater collaborations, and more individuals participating in dementia research.”
To learn more about Alzheimer’s Society research or to get involved, visit alzheimers.org.uk/research.
