Alzheimer's Disease Symptoms Reversed in Mice

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Scientific American

 

A cancer drug given to mice eliminates brain-damaging proteins, leading to improved cognition within days, but will it work in humans?

By Gary Stix

 

A nearly 13-year-old skin cancer drug rapidly alleviates molecular signs of Alzheimer's disease and improves brain function, according to the results of a new mouse study being hailed as extremely promising. Early-stage human clinical trials could begin within months.

In the study, published online February 9 by Science, researchers from Case Western Reserve University in Cleveland and colleagues used mice genetically engineered to exhibit some of the symptoms of Alzheimer's. Most notably, the mice produced amyloid beta peptides—toxic protein fragments that gum up neurons and lead to cell death—and showed signs of forgetfulness.

Amyloid beta (red areas) peptides clear from the brain of an Alzheimer's mouse after three days of treatment with a cancer drug (right image). Source: AAAS/Science
The Case Western team, led by Gary Landreth, decided to try the drug bexarotene (Targretin), approved in 1999 for cutaneous T cell lymphomas. The team chose this drug because of its long experience working with proteins in the nucleus of brain cells that can induce biochemical processes that affect amyloid beta.
Landreth and his colleagues fed bexarotene to the demented mice, and with just a single dose it lowered the most toxic form of the amyloid beta peptide by 25 percent within six hours, an effect that lasted for up to three days. Mice that were cognitively impaired by the amyloid buildup resumed normal behaviors after 72 hours: They began to crinkle toilet paper placed nearby to make nests, a skill lost as amyloid increased in their brains.
"We have successfully reversed all of the known pathological features and behavioral deficits found in mouse models of Alzheimer's disease," Landreth says. "Never before has anyone observed clearance of amyloid plaques with such speed in mouse models."
Other Alzheimer's researchers hail the work. "I think this is extremely promising," says Samuel Gandy, a professor of neurology and psychiatry at Mount Sinai School of Medicine and associate director of the hospital's Alzheimer's Disease Research Center. "One of the drugs that has been on our wish list for 25 years is a drug that would clear existing amyloid deposits."
"Landreth's paper is impressive," adds Kenneth Kosik, a neuroscientist at the University of California, Santa Barbara. "The effects in mice, including some restoration of cognitive abilities, are dramatic."
Neural sanitation
In a field littered with drug failures, the study offers hope that the strategy of clearing the brain of the toxic peptide can work. Bexarotene does not do so directly, however; instead, it activates retinoid receptors on brain cells that increase production of a fat-protein complex, apolipoprotein E, that helps rid excess amyloid in the fluid-filled space between neurons. It also appears to enhance another cleanup process, called phagocytosis.
Bexarotene functions differently than an amyloid-clearance approach using monoclonal antibodies, which are further down the drug development pipeline. These antibodies bind directly to amyloid and then remove it, but they have sometimes caused fluid to fill brain tissue. Bexarotene may be less likely to cause such swelling. "I think the fact that we're inducing a natural process by turning on these receptors doesn't lend itself to water on the brain," says Paige Cramer, Landreth's graduate student who performed much of the research. Unlike bexarotene, which is taken orally, monoclonals are more troublesome to administer, because they must be delivered intravenously, and if they receive U.S. Food and Drug Administration approval, they would likely be significantly more expensive.

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