Written by Lauren Robertson, Science Writer.
UCLA researchers have used a green tea molecule to identify potential drug candidates capable of breaking the protein tangles that cause Alzheimer’s (AD) and other neurodegenerative diseases. The research, published in Nature Communications, opens new avenues for structure-based drug discovery that could help find improved drug candidates targeting amyloid diseases.
The power of green tea
AD is the observed result of the protein, tau, aggregating into fibrils and attacking neurons. It is widely believed that by eliminating these fibres, through disaggregation, it might be possible to slow or halt the progression of AD. One molecule that is particularly good at breaking up these tau tangles is epigallocatechin gallate (EGCG) – a molecule derived from green tea.
“If we could break up these fibres, we may be able to stop death of neurons,” said David Eisenberg, UCLA professor of chemistry and biochemistry whose lab led the new research. “Industry has generally failed at doing this because they mainly used large antibodies that have difficulty getting into the brain. For a couple of decades, scientists have known there’s a molecule in green tea called EGCG that can break up amyloid fibres, and that’s where our work departs from the rest.”
Crossing the blood-brain barrier is one of the key challenges of any drug development pipeline for neurodegenerative disease. Though EGCG has been studied extensively, it has not yet been developed into a successful drug for treatment because it functions best in water and is not able to enter the brain very easily. It also has an affinity to lots of other proteins besides tau fibres, meaning by the time it does reach the brain, its efficacy is much weaker.
To see if there was any way to overcome these challenges, the researchers decided to try and figure out the mechanism behind EGCG’s disaggregation of tau amyloid.
In a (tau) tangle
They started by extracting tau tangles from the brains of deceased Alzheimer’s patients and incubating them with EGCG for varying periods of time. After 24 hours, all the fibres had disappeared. To understand how this was occurring, the team took fibrils from earlier in time and imaged them using cryo-EM microscopy.
They discovered that EGCG was snapping the fibrils into smaller, harmless pieces. “The EGCG molecules bind to each layer of the fibres, but the molecules want to be closer together. As they move together the fibre snaps,” Eisenberg said.
By elucidating the mechanism behind EGCG’s ability to break tau fibres, the team also learned that the EGCG molecules attached to “pharmacophores” – specific locations on the tau fibres. They then screened vast libraries of brain and nervous system-friendly small molecules to identify those that bound to the same sites.
The small molecules CNS-11 and CNS-17 were identified as being top potential drug candidates that not only broke up the tau fibres, but also stopped them spreading from cell to cell. In particular, the team would like to focus on CNS-11 in future research. “By studying variations of [CNS-11], we may go from this lead into something that would be a really good drug,” Eisenberg said.
In the future, this work may result in a whole new generation of AD drug leads that can enter the brain and break up tau fibrils – and this could be applicable to other degenerative conditions such as Parkinson’s.
