Dual-targeting drug stops tau accumulation in Alzheimer's disease

Summary: Scientists have developed a drug that targets both key aggregation-promoting sites of the tau protein, a key player in Alzheimer's disease. This peptide inhibitor, RI-AG03, is effective in preventing tau accumulation in laboratory studies and fruit flies, offering hope for new Alzheimer's treatments.

Unlike current drugs, RI-AG03 uniquely blocks both tau “hotspots,” potentially leading to safer and more targeted therapies. Researchers plan to test the drug on rodents before moving on to clinical trials.

Important facts:

• RI-AG03 blocks the buildup of tau protein and thus prevents neurodegeneration.
• It targets both major tau “hotspots” for aggregation, a novel approach.
• The drug extended the lifespan of fruit fly models of Alzheimer's disease.

Source: University of Southampton

An international team of researchers has made a promising breakthrough in the development of drugs to treat Alzheimer's disease.

For the first time, scientists have developed a drug that acts on both key aggregation-promoting “hotspots” of the tau protein, closing a critical gap in current treatments.

The drug, a peptide inhibitor called RI-AG03, was effective in preventing the formation of tau proteins – a key factor in neurodegeneration – in both laboratory and fruit fly studies.

The study published today [3 October 2024] In Alzheimer's and Dementia: The Journal of the Alzheimer's Association, was conducted by the University of Southampton in collaboration with Lancaster University, Nottingham Trent University, Tokyo Metropolitan Institute of Medical Science and UT Southwestern Medical Centre.

Dr. Anthony Aggidis, lead author of the paper, visiting researcher at the University of Southampton and former postdoctoral fellow at Lancaster University, said: “Our research represents an important step towards developing treatments that prevent the progression of diseases such as Alzheimer's disease can.”

“By targeting both key areas of the tau protein, this unique approach could help address the growing impact of dementia on society and provide a much-needed new option to treat these devastating diseases.”

A significant breakthrough

Tau proteins play a crucial role in maintaining the structure and function of neurons (brain cells). However, in Alzheimer's disease, these proteins fail and clump together into long, winding fibrils.

When the fibrils accumulate, they form so-called neurofibrillary tangles – masses of twisted tau proteins that clog neurons and prevent them from receiving the nutrients and signals they need to survive.

As more neurons die, memory, thinking, and behavior become more impaired, leading to the cognitive decline seen in Alzheimer's disease.

There are two specific “hotspots” of the tau protein where this clumping often occurs. While current treatments target one or other of these hotspots, RI-AG03 exclusively targets and blocks both.

“There are two regions of the tau protein that act like a zipper and allow aggregation,” says Amritpal Mudher, professor of neuroscience at the University of Southampton and one of the study’s lead authors.

“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.”

Targeted approach

The peptide-based approach is also more targeted than current treatments, potentially making it safer and with fewer side effects.

“We know that the toxicity of the tau protein is closely related to its ability to aggregate, so we expect desirable effects by inhibiting aggregation,” says Dr. Aggidis.

“However, current aggregation inhibitors have many side effects because they can affect the functions of many other proteins.

“RI-AG03 was specifically designed to target the tau protein, meaning it is less likely to cause unwanted interactions with other proteins.”

Testing RI-AG03

The article describes how RI-AG03 was first developed by Dr. Aggidis was developed in the laboratory of the late Prof. David Allsop using computational biology at Lancaster University and tested in laboratory dishes.

To test its effectiveness in cells of a living organism, researchers at the University of Southampton then administered the drug to fruit flies that had pathogenic tau. These fruit fly models of Alzheimer's disease were developed by Dr. Shreyasi Chatterjee, a lecturer at Nottingham Trent University.

The researchers found that the drug suppressed neurodegeneration and extended the flies' lives by about two weeks – a significant increase considering the insects' lifespan.

To understand what was happening, the Southampton scientists looked deep into the brains of the fruit flies.

Prof Mudher said: “When we didn't feed the flies the peptide inhibitor, they had lots of pathogenic fibrils grouped together in a ball. But when we gave them the drug, the amount of pathogenic fibrils decreased significantly.”

“The higher the dosage administered, the greater the improvement in the lifespan of the fruit fly.”

To make sure this wasn't just the case in fruit flies, researchers at UT Southwestern Medical Center tested the drug in a biosensor cell – a type of living human cell line engineered to detect the formation of pathogenic tau fibrils.

Here too, they found that the drug successfully penetrated the cells and reduced the aggregation of tau proteins.

The team expects their work to have a significant impact on drug discovery in neurodegenerative diseases and now plans to test RI-AG03 in rodents before moving on to clinical trials.

The research was funded by the Alzheimer's Society. Dr. Richard Oakley, deputy director of research and innovation, said: “Dementia is the leading cause of death in the UK and creates huge costs and pressures on our healthcare system. That’s why we’re committed to funding world-leading studies like this.”

“This research takes promising steps toward a new, unique therapy that targets tau, a harmful protein in the brains of people with Alzheimer's disease, and prevents 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.

“It's important to note that the study is still in its early stages, so we don't yet know whether it will work or be safe for humans, but it's an exciting development and we look forward to seeing where it goes she leads.”

“Research will beat dementia, but we need to make it a reality faster by providing more funding, creating more partnerships and getting more people involved in dementia research.” To find out more about or take part in Alzheimer's Society research, visit alzheimers.org.uk/research.”

About this news from neuropharmacology and Alzheimer's research

Author: Steven Williams
Source: University of Southampton
Contact: Steven Williams – University of Southampton
Picture: The image comes from Neuroscience News

Original research: Open access.
“A novel peptide-based tau aggregation inhibitor as a potential therapeutic agent for Alzheimer's disease and other tauopathies” by Anthony Aggidis et al. Alzheimer's and dementia

Abstract

A novel peptide-based tau aggregation inhibitor as a potential therapeutic agent for Alzheimer's disease and other tauopathies

INTRODUCTION

Since aggregation underpins tau toxicity, aggregation inhibitor peptides may have disease-modifying potential. They are therefore currently in development and are aimed at either ³⁰⁶VQIVYK³¹¹ aggregation-promoting hotspot that occurs in all tau isoforms or the ²⁷⁵VQIINK²⁸⁰ aggregation-promoting hotspot in 4R isoforms. However, for a tau aggregation inhibitor to be potentially clinically relevant to other tauopathies, it must target both hotspots to suppress aggregation of tau isoforms, be stable, cross the blood-brain barrier, and rescue aggregation-dependent tau phenotypes in vivo.

METHODS

We have developed a retroinverse stable D-aminopeptide, RI-AG03 [Ac-rrrrrrrrGpkyk(ac)iqvGr-NH2]based on the ³⁰⁶VQIVYK³¹¹ Hotspots that exhibit these disease-relevant features.

RESULTS

Unlike other aggregation inhibitors, RI-AG03 effectively suppresses the aggregation of multiple tau species containing both hotspots in vitro and in vivo, is nontoxic, and suppresses aggregation-dependent neurodegenerative and behavioral phenotypes.

DISCUSSION

RI-AG03 therefore meets many clinically relevant requirements for an anti-aggregation tau therapeutic and should be further investigated for its disease-modifying potential for tauopathies.