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By Aristos Georgiou
Science and Health Reporter
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Scientists say they have achieved a "first" in the development of drugs to treat Alzheimer's disease.
In a study published in the journal Alzheimer's & Dementia, a team of researchers report 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 specific proteins. In fruit fly models and lab experiments on human-derived cells, the team demonstrated that RI-AG03 was effective at preventing the harmful clumping of tau proteins—which is linked to neurodegeneration—by acting on two particular "hotspots."
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"The drug prevented tau clumping in human cells and also reduced symptoms of neurodegeneration and extended lifespan in living organisms," Anthony Aggidis, lead author of the paper with the University of Southampton, told Newsweek.
It is important to note the preliminary nature of the research; thus, the study's results should be treated with caution. Only a small proportion of drugs that show promise in the preliminary stages progress to the market as therapeutics.
Although fruit flies offer significant advantages in early testing due to their simplicity and the ability to screen compounds rapidly, translating these findings into effective human treatments is challenging. Differences between fly and human biology limit the reliability of some results when moving to clinical phases.
Despite this, fly models remain valuable in identifying therapeutic targets early on, particularly for genetic screening in complex diseases like cancer and neurodegenerative conditions.
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The global societal cost of dementia—of which Alzheimer's is the most common form—is predicted to increase to $2 trillion by 2030, highlighting the "pressing" need to develop disease-modifying treatments, according to the study authors.
Over the past few years, there has been significant interest in therapies that inhibit the aggregation of tau proteins. Several preliminary reports describe the promising potential of numerous small molecules that employ different mechanisms of action. But thus far, only one group of these compounds—known as methylene-blue derivatives—has been tested in human clinical trials, and failed to demonstrate effectiveness.
"While there is no doubt that small molecules employ different mechanisms to effectively reduce Tau aggregation, their utility as therapeutic agents are limited because their mode of action is invariably non-specific so they invariably impact other proteins and cause unwanted side effects," the authors of the study wrote.
This highlights the need to develop compounds that inhibit tau aggregation more specifically, they said.
Tau proteins play a key role in maintaining the structure and function of neurons or brain cells. But in the brains of patients with Alzheimer's disease, tau proteins malfunction and clump together.
"This clumping is toxic to the brain, and it kills brain cells, which results in memory loss and impaired thinking. This is well described in the literature and correlates strongly with disease progression," Aggidis told Newsweek.
Evidence suggests there are two specific "hotspots" that are responsible for the aggregation, or clumping.
"This aggregation is caused by two small regions within the protein, called 'hotspots' in this paper," Andrew Doig, a professor of Biochemistry at the University of Manchester in the U.K., who was not involved in the study, told Newsweek. "It seems likely that these hotspots stick to each other, causing the tau protein to assemble into toxic structures. A molecule that binds to one of these hotspots could therefore interfere with this assembly, stopping formation of the tau aggregates and reducing their toxicity."
According to the study authors, the newly developed compound is the "only" drug of its kind that inhibits the aggregation of tau by targeting both hotspots simultaneously.
In the study, the researchers found that the drug suppressed neurodegeneration and extended the lives of the fruit flies by around two weeks—a significant amount given their short life span of more than a month.
The authors also tested the drug in the lab in specially engineered human-derived cells modified to produce human tau protein. They found that RI-AG03 penetrated the cells and reduced the aggregation of tau proteins, too.
"What is new here, is that the authors have invented a molecule that binds to both tau hotspot regions. Hence, it could be more effective than other tau aggregation inhibitors that interact with just one of the hotspots. This is a fair claim, though how important binding to both hotspots might be in an Alzheimer's drug remains to be seen," said Doig.
"The work is carefully done and an interesting novel approach, as drugs that interfere with aggregation have had little success in clinical trials for Alzheimer's so far. The compound could potentially become a new Alzheimer's drug, though very many challenging steps need to be overcome before this is achieved."
The study authors said RI-AG03 should be investigated further in future studies using rodent models. Tests of this nature are essential before a drug can be tested in humans.
"This work is a long way from becoming a therapeutic that could benefit patients," Doig said. "The failure rate for Alzheimer's drugs in clinical trials is very high [some estimates suggest the figure is around 98/99 percent] though there have been some encouraging successes recently."
"Most Alzheimer's drugs that pass tests in animals fail in clinical trials in people. One reason could be that Alzheimer's is difficult to diagnose at its earliest stages, so drugs can only be given when it is too late for them to work. Earlier diagnostics that are in development might help."
Aggidis said his team acknowledged the challenges of translating findings from fruit fly models to humans but noted that the biological processes involving tau are conserved across species and use of such models is well established.
"The positive results we've observed give us confidence, but we understand that human trials can reveal complexities that aren't evident in pre-clinical models. Whether positive or negative is yet to be determined," he said.
Is there a health issue that's worrying you? Do you have a question about dementia? Let us know via health@newsweek.com. We can ask experts for advice, and your story could be featured on Newsweek.
Update 11/15/24, 5:41 a.m. ET: This article was updated with comment from Andrew Doig.
Reference
Aggidis, A., Devitt, G., Zhang, Y., Chatterjee, S., Townsend, D., Fullwood, N. J., Ortega, E. R., Tarutani, A., Hasegawa, M., Cooper, A., Williamson, P., Mendoza-Oliva, A., Diamond, M. I., Mudher, A., & Allsop, D. (2024). A novel peptide-based tau aggregation inhibitor as a potential therapeutic for Alzheimer's disease and other tauopathies. Alzheimer's & Dementia. https://doi.org/10.1002/alz.14246
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