Bexarotene, a drug approved by the U.S. Food and Drug Administration to treat skin cancer, stopped the primary nucleation step in the self-assembly of amyloid-beta-42 oligomers and delayed the formation of pathogenic aggregates that are associated with Alzheimer’s disease neurodegeneration using a unique strategy that could potentially identify other anti-Alzheimer’s drugs.
The researchers, from the University of Cambridge (England), Lund (Sweden) University, and the University of Groningen (the Netherlands), also found that bexarotene (Targretin) blocked the build-up of toxic amyloid-beta-42 (Ab42) aggregates as well as motility dysfunction in a nematode worm model (Caenorhabditis elegans) of Ab42-mediated toxicity (Sci Adv. 2016 Feb;2:e1501244. doi: 10.1126/sciadv.1501244).
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The researchers used a drug discovery strategy to screen a large set of drugs known to interact with amyloid-beta for molecules that could block the primary nucleation of Ab42 aggregates by analyzing the effects that the drugs had on Ab42’s formation into aggregates. This allowed them to determine potential drug candidates’ mechanism for preventing the build-up of toxic Ab42 aggregates.
Earlier animal studies of bexarotene had suggested that the drug could actually reverse Alzheimer’s symptoms by clearing Ab42 aggregates in the brain. But those earlier results, which were later called into question, were based on a completely different mode of action – the clearance of aggregates – than the one reported in the current study. Bexarotene was tested earlier in an unsuccessful 1-month, randomized, placebo-controlled phase II trial in patients with mild to moderate Alzheimer’s, but this new research suggests that the drug may need to be given very early in the disease.
“We anticipate that the strategy that we have described in this paper will enable the identification of further compounds capable of inhibiting Ab42 aggregation and the definition of the specific microscopic steps affected by each compound (that is, primary or secondary nucleation or elongation),” the researchers wrote. “The results described in the present work indicate that bexarotene and other inhibitors of primary nucleation have the potential to be efficient means of delaying aggregation by reducing the probability that primary nuclei are formed and proliferate, such that our natural protection mechanisms could remain effective to more advanced ages. Indeed, we draw an analogy between the strategy presented here and that of using statins, which reduce the level of cholesterol and thus the risk of heart conditions, and suggest that such molecules could effectively act as ‘neurostatins.’ ”
The research was supported by the Centre for Misfolding Diseases at the University of Cambridge. The authors said they have no conflicts of interest to declare.
