Sci. Aging Knowl. Environ., 17 December 2003
Out, Out, Damned Zinc
Metal-grabbing antibiotic might hinder Alzheimer's disease
Key Words: Alzheimer's Disease Assessment Scale Mini-Mental State Examination ApoE
Michael Jordan returned from retirement to lead the Chicago Bulls to three straight NBA championships, and researchers hope that a chemical can pull off a similarly splashy comeback and challenge Alzheimer's disease (AD). The first clinical trials of the drug, an antibiotic that was retired more than 30 years ago, suggest that it slows progression of the illness in the most severely affected patients. The work also supports the hypothesis that jumbled metal metabolism in the older brain promotes deterioration.
Researchers have long known that globs of the protein amyloid riddle the brains of AD patients, but they aren't sure what incites the pileups or how the illness saps brainpower. Neuroscientist Ashley Bush of Harvard Medical School in Boston and colleagues fault a buildup of metals (see "Mindful of Metal"). Copper, for example, adheres to and reacts with amyloid, spawning cell-damaging oxidants, the researchers suggest. Damaged amyloid proteins also stick together when prodded by zinc released from synapses. To test their hypothesis, in 2001 Bush and colleagues dosed mice that were genetically engineered to accrue amyloid plaques with an antibiotic called clioquinol, which scoops up copper and zinc. After 9 weeks, the treated mice carried almost half as much plaque as did untreated rodents.
Building on those results, the researchers gave clioquinol to 15 AD patients and compared their cognitive prowess to that of 16 AD sufferers who received a placebo. During the 9-month study, the team regularly measured the blood amounts of zinc, copper, and amyloid in both groups and gave the volunteers a standard test to gauge mental acuity. The exam requires patients to perform tasks such as recalling and recognizing words and copying shapes onto a piece of paper. Both groups deteriorated mentally during the study, and clioquinol did not slow this slide in the sharpest patients. But in the low scorers, the drug did restrain cognitive decay. Treated patients also carried more zinc in their blood, suggesting that clioquinol dislodges the metal from amyloid, allowing zinc to reenter the circulation. The researchers couldn't determine whether clioquinol dissolved plaques, but it did reduce the amount of amyloid in the bloodstream. In mice, falling blood concentrations of amyloid translate into reduced accumulation in the brain, Bush says.
"It's an exciting preliminary look at the effectiveness of clioquinol," says neuroscientist John Trojanowski of the University of Pennsylvania in Philadelphia. Bush and colleagues plan to launch a larger, longer trial that will track 100 AD sufferers over 12 months. He says that they are increasing the number of patients slowly to confirm the drug's safety. It was pulled from the market in 1970 because of rare side effects such as nerve damage and blindness, but Bush and colleagues think that vitamin B-12 injections can forestall those problems. Their research will indicate whether it's time to take clioquinol out of the old drugs' home and put it back into the clinical lineup.
December 17, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150