Sci. Aging Knowl. Environ., 15 September 2004
Iron glut clouds eyes in mice
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2004/37/nf85
Too much iron wrinkles vision, according to new work. Mice that lack two iron-oxidizing enzymes show signs of age-related macular degeneration (AMD), the most common cause of vision loss in elderly people. The study suggests that drugs that reduce iron amounts might prevent or slow the disease.
Risk of AMD increases with age, and 30% of folks over 70 show signs of the disease. The condition blurs and distorts central, as opposed to peripheral, vision. Perhaps because of oxidative damage to photoreceptors--cells that detect light--molecular garbage known as drusen accumulates between the retina and an underlying layer known as the retinal pigment epithelium (RPE). Over time, drusen can kill cells in the RPE, cutting off the nutrient supply to photoreceptors. In advanced AMD, fragile, leaky blood vessels infiltrate the retina, causing yet more harm. Previously, ophthalmologist Joshua Dunaief of the University of Pennsylvania in Philadelphia and colleagues observed that AMD patients have unusually high quantities of iron in their retinas, suggesting that accumulation of the metal could trigger the disease. Bolstering the idea, a rare inherited eye disease similar to AMD stems from a mutation in the gene that produces ceruloplasmin, a protein that converts iron from a reactive and destructive form to a gentler variety.
To test whether iron buildup spurs AMD, Dunaief and colleagues removed the genes for ceruloplasmin and a related protein, hephaestin, from mice. Animals that lacked either gene appeared normal, but mice missing both genes carried approximately four times more iron in their retinal cells than did normal animals. The rodents' retinas deteriorated over time, showing changes similar to those in the eyes of AMD patients. They lost normal coloring, photoreceptors and RPE cells died, and blood vessels grew inappropriately. The study suggests that an overload of iron helps spur AMD, says Dunaief, although other factors, such as an untamed inflammatory response, likely contribute. Next, he wants to test whether soaking up iron in the mutant animals maintains eye health. Dunaief notes that the metal also amasses in the brains of Alzheimer's disease (AD) patients, many of whom develop AMD; moreover, the protein amyloid clumps in AMD retinas as well as in AD brains. The two disorders are similar enough that drugs that prevent or treat one disease might guard against the other, he says: "It would be wonderful if it worked out that way."
"We've known for a long time that iron can be devastating to the eye," says neurobiologist Dean Bok of the University of California, Los Angeles. For instance, injecting iron into mouse eyes causes the retinas to degrade. But the new study suggests that disruptions in normal iron metabolism might contribute to AMD, he says. Bok cautions that these mice don't display all aspects of the disease. For one, they don't accrue drusen, a hallmark of AMD. Faulty iron regulation might not be a primary cause of AMD, but it could speed vision loss in susceptible people, he says. Further work discerning the role of iron in AMD might reveal ways to keep aging eyes looking sharp.
September 15, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150