Anti-cancer drug Bexarotene shows promise at preventing and delaying the onset of Alzheimer’s disease
New research on nematode worms and in a test tube indicates the statin-like drug, termed a ‘neurostatin’, can target the toxic cascade behind devastating neurodegeneration. The researchers involved tested the drug on the model organism C.elegans, which had been engineered to develop components of Alzheimer’s disease. They discovered Bexarotene was able to protect at risk worms from developing the disease but was ineffective in those who had already developed the condition.
“The body has a variety of natural defences to protect itself against neurodegeneration, but as we age, these defences become progressively impaired and can get overwhelmed. By understanding how these natural defences work, we might be able to support them by designing drugs that behave in similar ways”
How does it work?
Bexarotene appears to interfere with one of the first steps in the toxic cascade that leads to cell death – a process called primary nucleation. Nucleation refers to when proteins fold incorrectly and stick together forming clusters and fibril structures. In this case the culprit is amyloid beta, which has toxic effects if allowed to accumulate into oligomers and amyloid fibrils. While Alzheimer’s is a complex disease and many people are unconvinced amyloid is the key player, research has proven certain forms can indeed be harmful and lead to deterioration.
How did the researchers discover the drug?
The team assembled a library of over 10,000 molecules that interact with amyloid beta and might just prevent its aggregation. They focused on drugs already approved for other conditions, or those that had failed previous Alzheimer’s trials.
“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. It’s like traffic control – if you close a road to try to reduce jams, you can actually make the situation worse if you put the block in the wrong place. It is not necessarily the case that all the molecules in earlier drug trials were ineffective, but it may be that in some cases the timing of the delivery was wrong”
Prevention, not reversal
Previous research had demonstrated Bexarotene could clear amyloid beta aggregates, but had not shown significant results in trials in human patients with Alzheimer’s. The new research has highlighted a completely different molecular effect, one which is apparently more effective at prevention rather than reversal.
“We know that the accumulation of amyloid is a hallmark feature of Alzheimer’s and that drugs to halt this build-up could help protect nerve cells from damage and death. 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. We will now need to see whether this new preventative approach could halt the earliest biological events in Alzheimer’s and keep damage at bay in in further animal and human studies”
Long term human studies are now required to see if the drug has any preventative action in people. We know specific genes like ApoE can make people much more vulnerable to Alzheimer’s, so this type of drug could be beneficial in such patients. Perhaps in the future any effective preventative treatment could be commonplace in at risk age groups as a whole.
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