Cancer drug eases Alzheimer's in mice

A skin cancer drug can improve Alzheimer's-like symptoms in mice engineered to mimic the condition, it has been widely reported.

Many national newspapers have covered the news, which is based on animal tests involving the drug bexarotene (brand name Targretin), which is currently only used to treat a rare form of skin cancer. This drug was given to mice that had been genetically engineered to develop a condition similar to Alzheimer’s, and in a short space of time the mice showed lowered brain levels of a key protein called beta-amyloid. Beta-amyloid is the substance that forms the protein plaques in the brain that are characteristic of Alzheimer’s. The researchers also observed post-treatment improvements in the brain function of the mice – for example, they were better able to build nests and remember the way through a maze.

Although this research is in animals and there is limited direct application to humans at the current time, these early findings do show some potential for further research. Notably, the drug had a rapid effect on amyloid plaques that are characteristic of Alzheimer’s, and the fact that the drug is currently licensed means it will have undergone safety regulations for its current use. That said, there are no guarantees it will prove as safe or effective in people with Alzheimer’s.

At the current time no tests have been carried out in humans with Alzheimer’s, only an animal model of the disease. The research will undoubtedly be of interest to researchers, doctors, and patients and their families, but it is far too early to suggest that this could be a cure for Alzheimer’s.

Where did the story come from?

The study was carried out by researchers from Case Western Reserve University School of Medicine, Cleveland, and other institutions in the US. The study was supported by a number of research funding foundations, including the Blanchette Hooker Rockefeller Fund, Thome Foundation, and the Roby and Taft Funds for Alzheimer’s.

The study was published in the peer-reviewed journal Sciencexpress.

BBC News gives accurate coverage of this study. The Sun, Daily Mail and The Daily Telegraph featured slightly optimistic headlines, but their articles generally do make it clear that this was a study in mice and give good accounts of the research.

What kind of research was this?

This was animal research aiming to investigate the effects of a drug called bexarotene on a mouse model of Alzheimer’s disease.

Bexarotene activates a receptor on the surface of cells that is known to be involved in triggering the production of a protein called ‘apolipoprotein E’ (ApoE). The ApoE protein is involved in the breakdown of soluble beta-amyloid, a protein that builds up to form the characteristic insoluble plaques seen in the brains of people with Alzheimer’s.

All humans carry a gene containing the code for producing the ApoE protein, but some people carry a particular variant of the ApoE gene known as the ApoE e4 allele. People carrying this variant are known to be at increased risk of developing Alzheimer’s disease, and carrying this variant seems to be associated with the build-up of beta-amyloid plaques in the brain.

The researchers were interested whether a drug that increases production of ApoE could potentially have an effect on the build-up of beta-amyloid in the brain. To explore this possibility they decided to test the drug in mice with Alzheimer’s-like symptoms, looking at whether it could reduce their their beta-amyloid levels and improve their cognitive performance.

What did the research involve?

The researchers used various different genetically engineered mouse models of Alzheimer’s in their experiments. The researchers carried out a number of tests to assess the effects of bexarotene on soluble beta-amyloid in the fluid surrounding the brain, insoluble beta-amyloid plaques in the brain, and cognitive performance of these mice.

The mice were administered oral bexarotene for three, seven, nine, 14, 20 or 90 days. These mice were compared with similar mice that did not receive bexarotene. The researchers looked at mice of three different ages – two months, six months and 11 months – in order to look at the effects of the drug when given to mice at different stages of their Alzheimer’s-like condition: the older mice having more beta-amyloid protein build-up.

The mice in models of Alzheimer’s display impairments in their performance in several tasks: navigating a water maze (an indicator of cognition); nest construction (an indicator of social behaviour); fear response to placement in a shock chamber; and sense of smell. In a sample of mice the researchers tested performance in these four areas after administering the drug.

After the treatment periods the mice’s brains were examined to look for any changes.

What were the basic results?

The researchers found that administering a single dose of bexarotene gave a rapid reduction in levels of soluble beta-amyloid in the fluid surrounding the mice’s brains. There was a 25% reduction within 24 hours and this reduction was retained for over 70 hours. Up to 84 hours after treatment there was a return to pre-treatment levels of soluble beta-amyloid.

In six-month-old mice treated with bexarotene, insoluble beta-amyloid levels in the brain were reduced by 40% after 72 hours. When bexarotene was given to mice for longer periods of time they found a sustained reduction in beta-amyloid throughout the treatment period. They found comparable effects of the drug when testing in older, 11-month-old mice with greater beta-amyloid build-up.

The drug also improved the cognitive, social and sensory deficits of the mice:

• both six-month- and 11-month-old mice treated for seven days showed improvements in fear conditioning; the six-month-old mice also showed improvements in fear conditioning with 90 days of treatment
• performance in the water maze improved after 20- and 90-day treatment periods
• nest construction behaviour was restored after 72 hours of treatment
• ability to sense odours was restored by three days of treatment

How did the researchers interpret the results?

The researchers conclude that activation of the receptor involved (the retinoid X receptor) through use of bexarotene helps to clear beta-amyloid build-up in mouse models of Alzheimer’s and gives a rapid reversal of the associated cognitive and neurological deficits.

Conclusion

This animal research has demonstrated that bexarotene can have a positive effect in clearing the build-up of the characteristic beta-amyloid protein plaques and improving cognitive impairments in mouse models of Alzheimer’s. Bexarotene (brand name Targretin) is an anti-cancer drug that is currently licensed specifically for the treatment of a rare type of skin cancer called advanced cutaneous T-cell lymphoma.

Although this research is in animals, and therefore has a limited direct application to humans at present, these early findings do present some genuine potential that needs further research. There is bound to be great interest in the finding that the drug seemed to have an early effect on the amyloid plaques characteristic of Alzheimer’s, particularly as the study involved a drug that is already licensed for use in a specific, rare type of cancer (advanced cutaneous T cell lymphoma). Given its existing use, there may be the possibility of earlier testing in humans than there would be if this were a completely new chemical in development, which would have completely unknown health and safety effects. Nevertheless, this drug has not yet been tested in humans with Alzheimer’s, and results from such studies will be needed before we know for certain whether it is also helpful in humans.

Better treatments for Alzheimer’s in humans are needed, and research such as this is is an important early step towards achieving this goal. While it is far too early to say whether this drug could be a cure for Alzheimer’s, at least in the context of this early research the drug has marked itself out as a clear candidate for further exploration.