“First” success in Alzheimer’s with drug that hits hotspots

Scientists say they have achieved a “first” in developing drugs to treat Alzheimer’s disease.

In a study published in the journal Alzheimer's and dementiaA team of researchers reports the development of a new compound that they say is a “promising” candidate in the search for new therapies for neurodegenerative diseases such as Alzheimer's.

The compound, called RI-AG03, is a novel peptide inhibitor – a short chain of amino acids designed to block the activity of certain proteins. In fruit fly models and laboratory experiments on cells of human origin, the team showed that RI-AG03 effectively prevented the harmful clumping of tau proteins – which is linked to neurodegeneration – in two specific “hotspots”.

“The drug prevented tau clumping in human cells and also reduced symptoms of neurodegeneration and extended the lifespan of living organisms,” said Anthony Aggidis, lead author of the study at the University of Southampton Newsweek.

It is important to note the preliminary nature of the research; The results of the study should therefore be viewed with caution. Only a small proportion of the drugs that prove promising in the preliminary stage reach the market as therapeutics.

Although fruit flies offer significant advantages in early testing due to their simplicity and ability to rapidly test compounds, translating these findings into effective treatments for humans is challenging. Differences between fly and human biology limit the reliability of some results as they move into the clinical phase.

Nevertheless, fly models remain valuable for early identification of therapeutic targets, particularly for genetic screening in complex diseases such as cancer and neurodegenerative diseases.

The global societal cost of dementia – of which Alzheimer's is the most common form – is expected to rise to $2 trillion by 2030, underscoring the “urgent” need to develop disease-modifying treatments, the study authors said.

In recent years there has been great interest in therapies that inhibit tau protein aggregation. Several preliminary reports describe the promising potential of numerous small molecules that utilize different mechanisms of action.

So far, only one group of these compounds – so-called methylene blue derivatives – has been tested in human clinical trials and has not been able to demonstrate effectiveness.

“While there is no doubt that small molecules use different mechanisms to effectively reduce tau aggregation, their utility as therapeutic agents is limited because their mode of action is invariably nonspecific, so they invariably affect other proteins and cause unwanted side effects,” the study authors wrote.

This underscores the need to develop compounds that more specifically inhibit tau aggregation, they said.

Tau proteins play a key role in maintaining the structure and function of neurons or brain cells. But in Alzheimer's disease, the tau proteins fail and clump together.

“This clump is toxic to the brain and kills brain cells, causing memory loss and impaired thinking. This is well described in the literature and strongly correlates with disease progression,” Aggidis said Newsweek.

There is still some uncertainty about why tau begins to misfold and tangle in Alzheimer's and whether targeting these proteins alone could effectively treat the disease. Nevertheless, there is evidence that there are two specific “hotspots” where aggregation or clumping occurs.

According to the authors, the newly developed active ingredient is the “only” drug of its kind that inhibits tau aggregation by attacking both hotspots simultaneously.

“For the first time we have a drug that effectively inhibits both 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. Amritpal Mudher, one of the paper's lead authors and a professor of neuroscience at the University of Southampton in the United Kingdom, said in a press release.

In the study, researchers found that the drug suppressed neurodegeneration and extended the fruit flies' lives by about two weeks – a significant amount given their short lifespan of more than a month.

The authors also tested the drug in the laboratory in specially engineered human cells that were modified to produce human tau protein. They found that RI-AG03 entered the cells and also reduced the aggregation of tau proteins.

Although there is still a long way to go and several obstacles that need to be overcome before the drug can be tested in human clinical trials, the authors said that RI-AG03 is an “excellent” candidate for future research in this area.

They said it should be further investigated in future studies using rodent models, which generally provide a more insightful – although far from perfect – understanding of how a compound might work in the human body compared to fly models.

“Although we recognize the challenge of translating findings from fruit fly models to humans, the biological processes involving tau are conserved across species and the use of these models is well established,” Aggidis said. “The positive results we have observed give us confidence, but we understand that human trials can reveal complexities that are not apparent in preclinical models. Whether positive or negative is yet to be determined.”

“The drug is currently in preclinical testing. However, we believe the research will have a significant impact on drug discovery efforts in diseases such as Alzheimer's, allowing us to improve patient outcomes. Further preclinical experiments need to be conducted in more sophisticated models before consideration is given to conducting clinical trials.”

Is there a health problem that concerns you? Do you have a question about dementia? Let us know at [email protected]. We can ask experts for advice and your story could be featured on Newsweek.

reference

Aggidis, A., Devitt, G., Zhang, Y., Chatterjee, S., Townsend, D., Fullwood, NJ, Ortega, ER, Tarutani, A., Hasegawa, M., Cooper, A., Williamson, P., Mendoza-Oliva, A., Diamond, MI, Mudher, A. & Allsop, D. (2024). A novel peptide-based tau aggregation inhibitor as a potential therapeutic agent for Alzheimer's disease and other tauopathies. Alzheimer's and dementia.