Sci. Aging Knowl. Environ., 10 August 2005
Mice with Alzheimer's disease-linked gene variants suffer deteriorating retinas
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2005/32/nf63
A gene version that can lead to foggy thinking might also precipitate blurry vision, new results suggest. The gene variant, connected to Alzheimer's disease (AD) in humans, destroys the retinas of mice over time. The findings conflict with data from humans hinting that the gene protects eyes.
In age-related macular degeneration (AMD), the macula--the middle of the retina--clouds over, making central vision fuzzy. Scientists have implicated smoking, high-fat diet, and numerous genes in the disease. For instance, people are less likely to develop AMD if they carry a particular variety of the ApoE gene, called ApoE4. In contrast, ApoE4 boosts the risk of AD. The ApoE protein totes cholesterol, but no one knows why ApoE4 exacerbates AD and guards against AMD. To investigate the link between ApoE and sight, Malek and colleagues inserted the three human versions of the gene into mice, which have only one kind of their own ApoE gene.
The researchers generated several lines of mice, including one that carried two copies of the ApoE4 gene. In addition, they fed some individuals a high-fat diet. Young mice--12 to 30 weeks old--appeared to have healthy eyes, regardless of the genes they carried or the food they ate. But the retinas of 1 to 2 -year-old mice decayed. Animals with 2 copies of ApoE4 that munched high-fat chow showed discoloration, thickened membranes, and buildup of protein deposits in their retinas, similar to changes seen in AMD patients. In addition, 20% of the rodents exhibited fragile, leaky blood vessels, a characteristic of the so-called wet form of the disease. Retinas didn't degrade in genetically normal animals on a high-fat diet or in modified animals snarfing standard fare. Together, the findings suggest that a specific combination of genes and diet can increase the risk for AMD-like deterioration of the eyes. However, the observations contradict the results from humans, because ApoE4 harms rather than protects mouse eyes. The gene might behave differently in humans and mice, posit the authors, or the discrepancy could occur because each mouse had two copies of ApoE4. Only about 2% of humans carry two copies of that version. Fat intake might also explain the different results: In studies of ApoE and AMD in humans, researchers haven't addressed the effects of diet.
"It's quite surprising," because of the incongruity with the human studies, says geneticist Paul Baird of the University of Melbourne in Australia. Still, the ApoE mouse might provide the best rodent version yet of the human disease. To cause retinal trouble, researchers have previously damaged eyes with lasers or deleted or hyper-activated genes, says geneticist Rando Allikmets of Columbia University in New York City. The ApoE mouse "isn't as artificial" because the animals received the normal human gene. Next, he'd like to see the scientists mix and match ApoE4 with other ApoE varieties to more closely reflect how the versions are distributed in people. Investigators should also look at the combination of ApoE and the gene for complement factor H, he says. Alterations in this gene, which helps fight infection, increase AMD risk sevenfold, and ApoE might dampen or enhance this effect. Explaining the disparity between mice and humans might reveal new ways to provide a better forecast for aging eyes.
August 10, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150