A hallmark of Alzheimer’s disease is the formation of faulty protein clumps that clog up the brain and kill brain cells. Now, after observing its effects in a lab model of Alzheimer’s, scientists have discovered that an already approved anti-cancer drug could delay the onset of the neurodegenerative disease.
The drug – called bexarotene, approved in the US for the treatment of lymphoma – targets primary nucleation, the first step in the chain reaction that causes the faulty protein clumps or amyloid protein plaques, note the researchers, who report their findings in a Science Advances paper.
The team is not proposing bexarotene as a cure for Alzheimer’s disease; they suggest it could reduce the risk of developing the disease by boosting the body’s natural defences against faulty proteins in the brain.
Senior author Michele Vendruscolo, a professor in the department of chemistry at the University of Cambridge in the UK, explains that as we age, our natural mechanisms for defending against brain plaques get weaker and become overwhelmed. She adds:
“By understanding how these natural defenses work, we might be able to support them by designing drugs that behave in similar ways.”
He and his colleagues – including other researchers from Cambridge, the University of Groningen in the Netherlands and Lund University in Sweden – gave bexarotene to nematode worms that had been genetically programmed to develop symptoms of Alzheimer’s disease.
The team found bexarotene disrupted the first steps in the process of amyloid plaque formation. When given early enough, the drug completely suppressed the formation of the plaques in the worms.
However, the drug had no effect once Alzheimer’s symptoms had already appeared.
Further analysis of the molecular action of bexarotene revealed that it stops primary nucleation, the first step in the chain reaction that leads to amyloid plaque formation.
This step occurs when naturally occurring proteins fold into the wrong shape and attach to other proteins. The process produces thin filaments called amyloid fibrils and smaller clusters called oligomers, which are highly toxic to nerve cells and are thought to be responsible for brain damage in Alzheimer’s disease.
Research to prevent oligomer formation in Alzheimer’s has been going on for over 2 decades, without success, which Prof. Vendruscolo and colleagues attribute to not understanding exactly how the disease begins at the molecular level.
An important feature of the study is that the researchers established exactly what happens stage by stage in Alzheimer’s disease, and what might result if a particular stage were interrupted or switched off.
They managed to do this using a test they developed, which Prof. Vendruscolo says not only measures the rates of the overall process, but also of specific sub-processes. This means, he explains, “we can reduce the toxicity of the aggregates rather than simply stopping them forming.”
The team found bexarotene after searching a library of 10,000 small molecules they compiled by looking for compounds that interact with amyloid beta, a sticky protein molecule that plays a key role in the formation of plaques in Alzheimer’s disease.
Using the test they devised, the researchers first screened for drugs already approved for treating other diseases or for drugs developed for Alzheimer’s and similar conditions that had not passed clinical trials.
The first molecule they identified was bexarotene. The authors attribute the success of their find to the fact they were able to target bexarotene to a precise step in the plaque-formation process.
Earlier studies of bexarotene had suggested it could actually reverse Alzheimer’s symptoms by clearing amyloid beta aggregates in the brain. But these findings were eventually disputed. Prof. Vendruscolo and colleagues say their approach shows that while bexarotene may not clear up aggregates, it can prevent them occurring in the first place.
Co-author Prof. Chris Dobson, who runs a group based at the department of chemistry and is Master of St John’s College, at the University of Cambridge, explains that failure in the earlier trials does not mean you have the wrong molecule – the problem could be timing of delivery:
“Even if you have an effective molecule, if you target the wrong step in the process, you can actually make things worse by causing toxic protein assemblies to build up elsewhere.”
Dr. Rosa Sancho, head of research at Alzheimer’s Research UK, sums up the case for bexarotene:
“A recent clinical trial of bexarotene in people with Alzheimer’s was not successful, but this new work in worms suggests the drug may need to be given very early in the disease.”
She says only further animal – and then human studies – can show whether this new preventive approach could halt the earliest biological events in Alzheimer’s and keep damage at bay.
In the meantime, Medical News Today has recently learned that some middle-aged people who have experienced head injuries develop Alzheimer’s brain plaques, but not necessarily in the same areas as those affected by the disease.