Scientists have discovered the anti-cancer drug bexarotene may target the first step in the toxic chain activity that leads to the death of brain cells, paving the way to new Alzheimer’s therapies.
The study, conducted by an international team of researchers from the University of Cambridge in England, Lund University in Sweden, and the University of Groningen in the Netherlands, is titled “An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Aβ42 aggregates linked with Alzheimer’s disease,” and was published in the journal Science Advances.
Bexarotene, a third-generation retinoid, is an anticancer therapy approved by the U.S. Food and Drug Administration that has been found to delay the onset of Alzheimer’s, both in a test tube and in worms. Like statins, bexarotene is safe and widely used by those at risk for heart disease. However, this is the first study reporting its potential as a “neurostatin.”
Researchers observed that bexarotene delivery into worms genetically modified to develop Alzheimer’s disease was not effective once disease symptoms had already emerged. But when the drug was given before the onset of symptoms, the animals did not develop Alzheimer’s, suggesting that bexarotene or other similar molecules might be used to reduce the risk of the debilitating disease.
Specifically, the researchers found that bexarotene halts primary nucleation, the first stage in the molecular cascade that leads to brain cells’ death. This phenomenon occurs when soluble proteins fold into the incorrect shape and stick together with other proteins, forming thin amyloid fibrils, creating oligomers, smaller clusters that are toxic to nerve cells and cause the brain damage found in Alzheimer’s patients.
“The body has a variety of natural defences to protect itself against neurodegeneration, but as we age, these defenses become progressively impaired and can get overwhelmed,” the study’s senior author, Prof. Michele Vendruscolo of Cambridge’s Department of Chemistry, said in a news release. “By understanding how these natural defenses work, we might be able to support them by designing drugs that behave in similar ways.”
For two decades, researchers have been working to find effective treatments for Alzheimer’s that can halt the aggregation and proliferation of oligomers, but these attempts have failed due to a lack of exact knowledge of the underlying mechanics of Alzheimer’s development.
Using a test developed by Tuomas Knowles, professor of the Department of Chemistry, and Sara Linse, professor at Lund University, investigators determined what happens during each stage of Alzheimer’s development and what can occur if one of the stages is switched off.
“In order to block protein aggregation, we need accurate understanding of exactly what is happening and when,” Vendruscolo said. “The test that we have developed not only measures the rates of the process as a whole, but also the rates of its specific component sub-processes, so that we can reduce the toxicity of the aggregates rather than simply stopping them forming.”
Study first author Johnny Habchi and colleagues gathered over than 10,000 small molecules that interact with amyloid-beta, a critical molecule in Alzheimer’s. Using the test developed by Knowles and Linse, they identified bexarotene. “One of the real steps forward was to take a molecule that we thought could be a potential drug and work out exactly what it does. In this case, what it does is suppress primary nucleation, which is the aim for any neurostatin-type molecule,” Vendruscolo said. “If you stop the process before aggregation has started, you can’t get proliferation.”
By understanding how Alzheimer’s develops in the brain, scientists were able to target bexarotene to the correct point in the process. “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,” said study co-author Prof. Chris Dobson, Master of St John’s College, University of Cambridge. “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.”
Previous studies examining bexarotene have found that the drug could reverse some of the symptoms of Alzheimer’s by dissipating the aggregates of amyloid-beta in the brain; however, the results were based on a different mode of action – the clearance of aggregates – than the one described in this new study.
Utilizing the new approach, researchers can perform quantitative explorations of the process of amyloid-beta aggregation and can show that drugs, including bexarotene, could be developed as prevention treatments due to their capacity to inhibit the first step in the process of amyloid-beta aggregation in the brain.
“We know that the accumulation of amyloid is a hallmark feature of Alzheimer’s and that drugs to halt this buildup could help protect nerve cells from damage and death,” said Rosa Sancho, chief of research at Alzheimer’s Research U.K. “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 further animal and human studies.”
Over the next 35 years, the number of people with Alzheimer’s disease is predicted to go from 40 million to 130 million, 70 percent of them in middle- or low-income countries. “The only way of realistically stopping this dramatic rise is through preventive measures: Treating Alzheimer’s disease only after symptoms have already developed could overwhelm healthcare systems around the world.”
Natural defenses keep proteins in check as we get older, but these processes can become compromised and some proteins can slip through the safety net. Although neurostatins are not a cure for Alzheimer’s, researchers believe they can be used to reduce the risk for the disease by acting as a backup for the body’s biological protections against anti-misfolding proteins.
“You wouldn’t give statins to someone who had just had a heart attack, and we doubt that giving a neurostatin to an Alzheimer’s patient who could no longer recognize a family member would be very helpful,” Dobson said. “But if it reduces the risk of the initial step in the process, then it has a serious prospect of being an effective preventive treatment.”
But is there hope for those already affected by the disease? These research methods have enabled scientists to identify compounds that, rather than preventing the disease, could slow down its progression even when symptoms have become evident. “The next target of our research is also to be able to treat victims of this dreadful disease,” said Vendruscolo.
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