An international team of researchers led by Lancaster University has made a promising discovery in the development of drugs to treat Alzheimer’s disease. For the first time, scientists have developed a drug that targets both major “hotspots” that promote aggregation of the tau protein in the brain, a key driver of neurodegeneration.
A new hope for the cure of Alzheimer’s disease
The drug, a peptide inhibitor called RI-AG03, was effective in preventing the accumulation of tau proteins in both laboratory and fruit fly studies.
The research, published on Alzheimer’s & Dementia was conducted by Lancaster University in collaboration with the University of Southampton, Nottingham Trent University, the 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 Lancaster University’s Faculty of Biomedical and Life Sciences.
The article describes how RI-AG03 was first developed by Dr. Anthony Aggidis in the laboratory of the late Professor Allsop, using computational biology, where it was tested in laboratory cultures.
The lead author, Dr. Aggidis, a former postdoctoral research associate at Lancaster University and visiting researcher at the University of Southampton, said: “Our research represents an important step towards creating treatments that can prevent the progression of diseases such asAlzheimer’s. By targeting both key areas of 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.”
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 twisted fibrils. When fibrils build up, they create what are called neurofibrillary tangles, masses of twisted tau proteins that clog neurons, preventing them from receiving the nutrients and signals they need to survive.
As more neurons die, memory, thinking and behavior become increasingly impaired, leading to the cognitive decline typical of Alzheimer’s.
There are two tau protein-specific “hot spots” where this aggregation tends to occur. While current treatments target one or the other of these hot spots, RI-AG03 uniquely targets and blocks both.
Amritpal Mudher, professor of neuroscience at the University of Southampton, said: “There are two regions of the tau protein that act like a zipper to allow it to aggregate. For the first time, we have a drug that is effective at inhibiting both of these regions. 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.”
The peptide approach is also more targeted than current treatments, making it potentially safer and with fewer side effects.
The Dr. Aggidis said: “We know that the toxicity of the tau protein is closely linked to its ability to aggregate, so by inhibiting aggregation we expect to see desirable effects. 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 is less likely to interact in unwanted ways with other proteins.”
To test its effectiveness in the cells of a living organism, researchers at the University of Southampton then administered the drug to fruit flies that had pathogenic tau. These Alzheimer’s disease fruit fly models were generated by Dr. Shreyasi Chatterjee, a lecturer at Nottingham Trent University.
The researchers found that the drug suppressed neurodegeneration and extended the lives of the flies by about two weeks, a significant extension considering the lifespan of these insects.
To understand what was happening, the Southampton scientists looked deeply into the brains of fruit flies.
Professor Mudher said: “When we didn’t feed the flies the peptide inhibitor, they had lots of pathogenic fibrils, which clump together to form a tangle. But when we fed them the drug, the pathogenic fibrils significantly decreased in quantity. The higher the dosage administered, the greater the improvement we saw in the fruit fly’s lifespan.”
To make sure it wasn’t exclusive to 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. Again, they found that the drug successfully penetrated cells and reduced the aggregation of tau proteins.
The team believes 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 Dr. Richard Oakley, associate director of research and innovation at the Society, said: “Dementia is the leading cause of death in the UK and places enormous costs and pressures on our healthcare system… This research is making promising steps towards a new therapy unique in its kind that targets tau, a harmful protein in the brains of people with Alzheimer’s, preventing its aggregation. 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.
“Importantly, 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 can’t wait to see where it takes us.
“Research will defeat dementia, but we need to make this a reality sooner rather than later through more funding, more partnerships and more people taking part in dementia research.”
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