Breakthrough Alzheimer’s drug successfully blocks both major disease ‘hotspots’ at once for the first time
RESEARCHERS have developed a drug that successfully blocks two major Alzheimer’s disease “hotspots” at once, in a “promising” breakthrough against the brain robbing disease.
The drug – called RI-AG03 – targets spots in the brain that promote the abnormal buildup of tau, a protein that forms “tangles” around cells and is a key driver in the decline of brain function.
There are two specific “hotspots” where tau protein clumping tends to happen.
Current treatments tend to single out one spot or the other, but RI-AG03 can target and block tau aggregation in both, Lancaster University scientists said.
The research team – which also included scientists from the University of Southampton, Nottingham Trent University, Tokyo Metropolitan Institute of Medical Science and the University of Texas Southwestern Medical Centre – tested out the drug in lab dish studies and on fruit flies.
It said RI-AG03 was effective at preventing the build-up of tau proteins in both.
Lead author Dr Anthony Aggidis 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.”
Tau proteins play a crucial role in maintaining the structure and function of brain cells, called neurons.
But in Alzheimer’s disease, these proteins malfunction, clumping together to form long, twisting fibres that clump together to form tangles.
These tau clumps 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.
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 enable it to aggregate.
“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.”
To test the drug’s effectiveness in cells within a living organism, researchers at the University of Southampton gave the drug to fruit flies with tau clumps characteristic of Alzheimer’s disease.
They found the drug suppressed neurodegeneration and extended the lives of the flies by around two weeks.
This might not seem like much in human terms, but it’s significant considering that the average fruit fly tends to live for about 30 days.
Scientists then looked into the brains of the fruit flies to understand how the drug was working.
Prof Mudher said: “When we didn’t feed the flies with the peptide inhibitor [RI-AG03], 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 the drug wasn’t only effective in fruit flies, researchers at the University of Texas Southwestern Medical Centre tested it in a biosensor cell – a type of living human cell line that’s engineered to detect tau tangle formation.
Here too, they found the drug successfully penetrated the cells and reduced the clumping of tau proteins.
Other major Alzheimer's breakthroughs
While experts have warned that dementia diagnoses in England have reached record numbers, there have been a number of recent advances against brain robbing diseases.
From “game-changing” drugs gaining approval to blood tests that can spot the condition years before symptoms, here are other major Alzheimer’s breakthroughs.
- A “game-changing” Alzheimer’s drug called donanemab, that slows mental decline by up to 60 per cent has been approved in the United States. A UK decision on whether the drug will become available to patients in the UK with early symptoms is expected imminently.
- A blood test that detects Alzheimer’s up to 15 years before symptoms emerge is set to be made free on the NHS within a year. The new test is cheaper, easier and at least as accurate as the current diagnosis options and works by measuring levels of a protein in the blood called p-tau217.
- Researchers have developed a first-of-its-kind test that could predict dementia up to nine years before a diagnosis, with 80 per cent accuracy. It involves analysing network of connections in the brain when it’s in “idle mode” to look for very early signs of the condition.
- Scientists have also put AI to the test, developing machine learning models were able to spot early warning signs of the memory-robbing condition up to seven years before Alzheimer’s symptoms appear.
- A woman who has evaded Alzheimer’s disease despite half her relatives getting it could hold the clues to how to prevent it, with scientists pinpointing a particular gene which they think could help prevent Alzheimer’s from progressing.
Researchers claimed their peptide-inhibiting drug is also more targeted than current treatments, potentially making it safer, with fewer side effects.
Dr Aggidis said: “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.
“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.”
Dr Richard Oakley, Associate Director of Research and Innovation at Alzheimer’s Society, added: “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.”
But he noted that more research needs to be done on RI-AG03.
“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,” Dr Oakley said.
The study was funded by Alzheimer’s Society UK and published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.