New Alzheimer's Treatment Shows Promise by Dual-Targeting Tau Protein

In a world-first, researchers have developed a drug that targets both critical regions of the tau protein, a key factor in Alzheimer's disease. The study, published in Alzheimer's & Dementia, has promising results in early-stage testing.

Alzheimer's disease is linked to tau protein

Over 55 million people suffer from dementia around the world, with the most common type, Alzheimer's disease (AD), contributing to around 60-70% of cases.. The progressive condition results in brain damage that leads to memory loss, language difficulties, thinking/ reasoning problems and changes in mood.

The exact cause of AD remains unclear. However, research has identified that the build-up of two key substances inside the brain, called amyloid and tau, plays a critical role in its pathogenesis. These substances form abnormal structures that are believed to damage and kill neurons resulting in the development of AD.

Although there is no cure for AD, there are treatments that work to temporarily reduce the symptoms. Many of the current therapies work by targeting tau proteins to prevent them from clumping together and forming neurofibrillary tangles.

“There are two regions of the tau protein that act like a zipper to enable it to aggregate,” said co-corresponding author Dr. Amritpal Mudher, a professor of neuroscience at the University of Southampton.

Many treatments work by acting on one or the other of these regions. However, until now, there has not been a product that can act on both simultaneously. Additionally, these drugs can be imprecise and affect other proteins in the brain, which can lead to unwanted side effects.

Targeting both regions on tau proteins

Using computational biology, lead author Dr. Anthony Aggidis, a visiting researcher at the University of Southampton and former postdoctoral research associate at Lancaster University, first developed a novel molecule called RI-AG03 to inhibit both critical regions on tau proteins. The drug was originally tested in lab dishes before being administered to fruit flies that had pathogenic tau.

The drug suppressed neurodegeneration and extended the flies' lifespan by around two weeks.

“When we didn’t feed the flies with the peptide inhibitor, they had lots of the pathogenic fibrils, which group together to make up a tangle. But when we fed them with the drug, the pathogenic fibrils decreased significantly in quantity,” said Mudher.

Mudher and their colleagues observed that, the higher the dosage administered, the bigger the increase in the fruit flies’ lifespan.

The team also tested the drug in a biosensor cell, which is designed to detect pathogenic tau fibril formation, and the drug successfully reduced the aggregation of tau proteins.

The dual-targeting approach is also more targeted than current treatments, making it potentially safer.

“RI-AG03 is specifically designed against the tau protein, meaning it’s less likely to undesirably interact with other proteins,” said Aggidis.

An important step toward creating treatments that can prevent the progression of AD

“For the first time, we have a drug which is effective in inhibiting both regions. This 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,” said Mudher.

“By targeting both of the key areas on the tau protein, this unique approach could help address the growing impact of dementia on society, providing a much-needed new option for treating these devastating diseases,” added Aggidis.

The study is still in its early stages, so it is yet to be determined whether RI-AG03  will be safe or if it will work in humans. Nonetheless, the study marks a promising development.

Reference: Aggidis A, Devitt G, Zhang Y, et al. A novel peptide‐based tau aggregation inhibitor as a potential therapeutic for Alzheimer’s disease and other tauopathies. Alzheimer’s Dementia. 2024:alz.14246. doi: 10.1002/alz.14246

This article is a rework of a press release issued by the University of Southampton. Material has been edited for length and content.