- Scientists have developed a new drug that targets two key regions of the tau protein, a major contributor to Alzheimer’s disease.
- The drug, a peptide inhibitor called RI-AG03, successfully prevented the build-up of toxic tau proteins in both laboratory and fruit fly studies.
- Although further research is necessary, including clinical trials in humans, this research contributes to the advancement of more effective therapies for neurodegenerative diseases.
Tau proteins are essential for maintaining the structure and function of neurons. However, in Alzheimer’s disease, these proteins malfunction and aggregate into long, twisted fibrils.
As these fibrils build up, they form neurofibrillary tangles — masses of tangled tau proteins that block neurons from receiving necessary nutrients and signals.
This leads to neuronal death, resulting in progressive memory loss, cognitive impairment and behavioural changes characteristic of Alzheimer’s disease.
A recent study, published in Alzheimer’s & Dementia, experimented with a new way of potentially preventing the build-up of toxic tau in the brain.
The study was conducted by researchers from the University of Southampton, in collaboration with Lancaster University, Nottingham Trent University — all in the United Kingdom — as well as the Tokyo Metropolitan Institute of Medical Science in Japan, and UT Southwestern Medical Centre, TX.
There are two main “hotspots” on the tau protein, where fibril clumping occurs. In this new study, researchers developed a drug that targets both of these “hotspots” of the tau protein.
While existing treatments focus on one or the other, RI-AG03 is the first drug to target and inhibit both.
The drug, which is a peptide inhibitor, successfully prevented the accumulation of tau proteins in both laboratory and fruit fly studies.
Anthony Aggidis, PhD, lead author and visiting researcher at the University of Southampton explained the key findings to Medical News Today.
“In Alzheimer’s disease, there is a protein in the brain that malfunctions by clumping together. This clumping is toxic to the brain and it kills brain cells, which results in memory loss and impaired thinking. For the first time, we have a drug that is effective at targeting both key regions of this protein which are responsible for it clumping together.”
The study details how RI-AG03 was first developed by Aggidis in the lab of the late David Allsop, PhD, using computational biology at Lancaster University, where it was initially tested in lab dishes.
To assess its effectiveness in living organisms, researchers at the University of Southampton administered the drug to fruit flies with pathogenic tau.
“We found that the drug suppressed neurodegeneration and extended lifespan by [approximately] 2 weeks in fruit flies [that] were bred to produce this malfunctioning human protein,” Aggidis explained. “This is a significant extension considering the life span of the insects.”
“While testing in fruit flies may appear strange, the biological processes involving this protein are conserved across species and use of these models is well established,” he added.
Upon examining the brains of the fruit flies, the researchers found that while flies fed the peptide inhibitor had large amounts of pathogenic tau fibrils, those treated with the drug showed a significant reduction in these fibrils.
The higher the dosage, the greater the improvement in the flies’ lifespan.
To ensure the effect was not exclusive to fruit flies, researchers at UT Southwestern Medical Center tested RI-AG03 on a biosensor cell, a type of human cell line engineered to detect tau fibril formation.
The drug successfully penetrated these cells and reduced tau aggregation.
James Giordano, PhD, Pellegrino Center Professor of Neurology and Biochemistry at Georgetown University Medical Center, who was not involved in this research, told MNT that “this is an interesting, well-conceived, and well-executed study that describes the development of a novel, pharmacologic agent, RI-AGO3.”
The drug “inhibits the aggregation of tau proteins that may be contributory to pathogenic changes in neurodegenerative diseases, such as Alzheimer’s [disease],” he explained.
“Using both in vitro and in vivo models this new agent shows promise in being able to reduce the aggregation of tau proteins by targeting two distinct sites and mechanisms operative in tau proliferation, while simultaneously being nontoxic to cells,” said Giordano.
Giordano explained that “this study further strengthens prior, and ongoing work, inclusive of our own research, that [firstly,] tau protein is operative in Alzheimer’s disease, and [secondly, the] inhibition of tau protein aggregation can be an important factor in development of interventions that may mitigate the development and progression of certain neurodegenerative diseases.”
“While this study is preliminary, its demonstrated outcomes in both in vitro and in vivo models provide support for the potential value of this, and related compounds in clinical therapeutics,” he added..
While further research is needed, the research team believes these findings will significantly influence drug discovery in the field of neurodegenerative diseases.
As a result, they now plan to test RI-AG03 in rodents before moving on to clinical trials.
“The drug is currently in preclinical 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. We are conducting additional pre-clinical tests over the next few years before considering clinical trials and how it may affect patients.”
– Anthony Aggidis, PhD
However, Clifford Segil DO, a neurologist at Providence Saint John’s Health Center in Santa Monica, CA, also not involved in the study, pointed out that “tau-centered disease modifying therapies have not panned out to produce any therapeutic agents to date and I am not expecting this research to result in any new neurological treatments.”
“Even once tau aggregation inhibitors can be found to work and be safe these will then need to be studied to see if they can cause any discernible clinical improvements in patients with neurological symptoms,” Segil added.
While these early findings are promising, it is important to note that drug development is a lengthy process and clinical trials in humans will be essential to determine the safety and efficacy of any potential treatments.
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