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—in two particular “hotspots.”
“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.
University of Southampton
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.
Thus far, only one group of these compounds—known as methylene-blue derivatives—has been tested in human clinical trials and has 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 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.
There is still some uncertainty about why tau starts to misfold and tangle in Alzheimer’s and whether targeting these proteins alone could effectively treat the disease. Despite this, evidence suggests that there are two specific “hotspots” where aggregation, or clumping, tends to happen.
According to the authors, the newly developed compound is the “only” drug of its kind that inhibits the aggregation of tau by targeting both hotspots simultaneously.
“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,” Amritpal Mudher, one of the lead authors on the paper and a professor of neuroscience at the University of Southampton in the United Kingdom, said in a press release.
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.
While there is a long way to go and several obstacles to overcome before the drug can be tested in human clinical trials, the authors said RI-AG03 is an “excellent” candidate for future exploration in this field.
They said it should be investigated further in future studies using rodent models, which generally provide a more insightful—albeit by no means perfect—understanding of how a compound might work in the human body compared to fly models.
“While we acknowledge the challenges of translating findings from fruit fly models to humans, the biological processes involving tau are conserved across species and use of these models is well established,” Aggidis said. “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.”
“The drug is currently in pre-clinical testing; however, we believe that the research will have a significant impact on drug discovery efforts in the field of diseases like Alzheimer’s so that we can improve patient outcomes. Additional pre-clinical experiments need to be conducted in more sophisticated models before considering conducting clinical trials.”
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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