Researchers have discovered that a drug currently used to treat cancer may also be effective at preventing the development of Alzheimer’s disease. Though the compound in question – called bexarotene – has been found to be ineffective at treating the condition once symptoms have presented themselves, a new study suggests that it could stave off the disease if administered before these tell-tale signs appear.
Alzheimer’s is a degenerative neurological condition that occurs when proteins called amyloid-beta clump together to form plaques, which cause damage to neurons in the brain. Preventing or reversing this process has therefore been identified as a potential pathway for the treatment of the disease.
Publishing their findings in the journal Science Advances, scientists from the U.K., Sweden, and Holland sought to identify compounds that might be capable of achieving just that. In particular, they focused on finding a way to prevent the self-assembly of a particular type of amyloid-beta, called amyloid-beta-42, into plaques, as this variant has been shown to be a major driver of Alzheimer’s.
To do so, they searched through four small-molecule databases in order to identify 16,850 molecules which contain groups that are likely to react with amyloid-beta-42 proteins. In doing so, these compounds may be capable of preventing the aggregation of these proteins by stopping them from folding in on themselves – a process called nucleation. Of the huge number of molecules identified, 386 were already FDA-approved drugs, some of which had previously been trialed as possible treatments for Alzheimer’s.
While all of these had been shelved after failing to pass these trials, the team behind this latest study suspected that their lack of success may have been partially down to a paucity of knowledge about how amyloid-beta proteins aggregate to form plaques. In 2012, the same researchers published a paper suggesting that this may occur in several stages, with the misfolding of proteins representing the initial phase.
According to their paper, this is followed by a "secondary nucleation" stage, during which these initial plaques provide a surface that catalyzes the formation of further plaques. The researchers therefore suggest that in order to treat Alzheimer’s, it may be necessary to prevent primary nucleation from taking place, and hypothesize that previous trials may have failed because drugs were administered once this had already occurred. In other words, these trials had sought to prevent secondary nucleation, rather than primary nucleation, from occurring.
Amyloid plaques are a major marker of Alzheimer's. Juan Gaertner/Shutterstock
Among the FDA-approved compounds identified by the researchers was bexarotene, which the researchers administered to nematode worms – model lab organisms – that had been genetically engineered to develop amyloid-beta plaques. In the absence of the drug, the worms became unable to bend after two days, as the formation of these plaques around their muscles left them paralyzed. However, the administration of bexarotene to mature worms caused this to occur after nine days, suggesting that the drug slowed down but did not prevent the formation of these plaques.
When administered during the larval stage of the nematodes’ life cycle, the development of plaques was completely averted, indicating that the drug may be effective at preventing Alzheimer’s from developing if used before primary nucleation occurs.
Although this effect has so far only been observed in nematodes, the researchers are hopeful that bexarotene could be used to treat Alzheimer’s in humans. Indeed, study coauthor Chris Dobson said in a statement that if the drug “reduces the risk of the initial step in the process, then it has a serious prospect of being an effective preventive treatment.”
