February 15, 2012
Alzheimer’s disease damages brain tissue in a variety of ways, but one of the most important seems to be the buildup of “plaques.” The deposits contain protein called beta-amyloid. Normally, beta-amyloid is produced and then removed at a more or less constant rate, but not in individuals with Alzheimer’s disease.
Beta-amyloid is normally removed from the brain with the help of a molecule called apolipoprotein. One version of this molecule, ApoE, increases a person’s risk of Alzheimer’s and appears to be linked to beta-amyloid buildup.
Meanwhile there is bexarotene, a chemical used in cancer treatments (officially for cutaneous T-cell lymphoma but unofficially for some other cancers). Researchers at Case Western Reserve University School of Medicine used bexarotene in mice that have a condition similar to human Alzheimer’s to change the relationship between ApoE and beta-amyloid. The drug caused plaques to be removed from much of the neural tissue. The behaviors of the mice on learning and memory tasks also changed in ways indicating that the effects of the Alzheimer’s-like condition was reversed, at least partially. A mere 72 hours of treatment with bexarotene “cured” misdirected nesting behavior and caused improvement in other tasks. Olfactory sense improved in some of the mice over a nine-day period.
There are reasons to be very positive about this result, but also reasons to be very cautious. Among the reasons to be cautious are:
- Mice are not humans, so there may be important but subtle differences in brain chemistry that will cause this treatment to not work the same way in humans.
- Although mice improved behaviorally, it is difficult to match mouse and human forms of “dementia,” so we must be cautious in interpreting the meaning of improvement in the mice.
- As far as I can tell, the effects of this treatment may be only short-term. Even though bexarotene has been used widely on humans, the dose and treatment approach needed for addressing human Alzheimer’s may be very different. It could even be dangerous or implausible.
- The ApoE contribution to Alzheimer’s is only one part of the disease. It may well be that the best-case scenario of a treatment based on this research would be only a partial cure, or only for some individuals.
Reasons to be optimistic include:
- The result seen in the mice was dramatic and fast. Half the plaques were removed in 72 hours, and over the long term, 75 percent were removed.
- Bexarotene is a drug already approved for use (in other areas of treatment) by the FDA, so the process of investigating this drug’s efficacy and safety is much more advanced than if it was some chemical not previously used on humans.
- Even if it turns out that this drug will not be usable on humans to treat this condition, a result like this strongly indicates a path for further research to develop similar treatments.
The researchers are optimistic. Paige Cramer, first author of the study, noted in a press release, “This is an unprecedented finding. Previously, the best existing treatment for Alzheimer’s disease in mice required several months to reduce plaque in the brain. Research team leader Gary Landreth notes that “this is a particularly exciting and rewarding study because of the new science we have discovered and the potential promise of a therapy for Alzheimer’s disease. We need to be clear; the drug works quite well in mouse models of the disease. Our next objective is to ascertain if it acts similarly in humans. We are at an early stage in translating this basic science discovery into a treatment.”
A lot of research related to disease seems to be reported in press releases and elsewhere with more optimism than deserved, but in my opinion this is a case where the new research is more closely linked to potential treatment than is often the case. Keep an eye on this story!
Cramer, Paige E. John R. Cirrito, Daniel W. Wesson, C. Y. Daniel Lee, J. Colleen Karlo, Adriana E. Zinn, Brad T.
Casali, Jessica L. Restivo, Whitney D. Goebel, Michael J. James, Kurt R. Brunden, Donald A. Wilson, Gary E. Landreth. (2012). ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD
Mouse Models. Science. Science Express 9 February 2012. DOI: 10.1126/science.1217697
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