A cancer drug known as bexarotene was thought to have promise working against Alzheimer’s disease in mice, and began early clinical trials. However, a new study has put forward confusing results. Within a novel mouse model of AD, the disease appears to mimic the genetics and pathology of the human disease more completely than any other animal model. Bexarotene was found to reduce the levels of the protein amyloid-beta within experimental mice that had late-stage Alzheimer’s, and the protein levels were increased during the earlier stages. Researchers at the University of Illinois at Chicago College of Medicine presented the finding, and Mary Jo LaDu reported the results on July 16th during the Alzheimer’s Association International Conference in Copenhagen. Back in 2012, LaDu developed a transgenic mouse which currently carries a human gene that can increase the disease risk 15-fold, and is considered the most important genetic risk factor known for the disease.
Currently, Alzheimer’s disease is the most common form of dementia, and has hallmark signs of dense plaques in the brain that are composed of amyloid-beta proteins. However, new research has shown that smaller, more soluble forms of the protein are responsible for nerve cell death leading to cognitive decline, rather than solid plaques. Within humans, there is a gene that produces a protein within cells known as apolipoprotein E, and aids in clearing amyloid-beta protein from the brain by binding to it and breaking it down into smaller pieces. LaDu’s mice carry a gene variant known as APOE4, or APOE3. LaDu, professor of anatomy and cell biology at UIC, discussed that previous studies showed in comparison to APOE3, the apolipoprotein produced by the APOE4 gene did not bind as well to amyloid-beta, and did not clear the neurotoxin from the brain as it should have.
Previous studies that involved bexarotene’s effect in mice of AD have shown mixed results, and it was only the UIC research that was presented in Copenhagen to be the very first study to use mice that carried a human APOE gene, and to also develop similar AD pathology. LaDu worked alongside Leon Tai, a research assistant professor in anatomy and cell biology, and their coworkers to administer bexarotene to mice that carried either APOE4 or APOE3 for seven days during the early, intermediate, or late stages of the disease. The researchers then were able to measure the levels of soluble amyloid-beta within the brains of the mice. Results of the study showed that mice that carried human APOE4 that were in late-stage, there was a 40 percent reduction of soluble amyloid-beta, and an increase in the binding of the apolipoprotein to the amyloid-beta. However, in mice that carried either APOE3 or APOE4, and were earlier-stages, there was actually an increase in the amount of soluble amyloid-beta protein. When the APOE4 mice were given bexarotene for a month starting at early-stage AD, there was no beneficial effect in preventing the disease from progressing.
More research is needed to determine the proper length and timing of the bexarotene treatment, and whether it will benefit APOE3 carriers, and if APOE4 carriers will have beneficial short-term treatments. Bexarotene is also extremely toxic to the liver, and may not be useful during long-term studies, due to the toxicity concerns, and the dosing during AD studies would need to be completely controlled, and the patients closely monitored.
- University of Illinois at Chicago. (2014, July 16). Drug’s effect on Alzheimer’s may depend on severity of disease. ScienceDaily. Retrieved July 16, 2014 from www.sciencedaily.com/releases/2014/07/140716123450.htm
By Lauren Horne
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