NEWS

St. Louis, Nov. 12, 1996 -- A paper in today's Proceedings of the National Academy of Sciences describes the first animal model for studying the progression of Down syndrome. The mouse also will aid research on Alzheimer's disease, the investigators say.

"As well as observing behavior in these mice that resemble a mental retardation, we find

age-related changes in the brain that are like some of those that occur in Alzheimer's disease," says lead author David M. Holtzman, M.D., assistant professor of neurology and of molecular biology and pharmacology at Washington University School of Medicine in St. Louis.

One in every 800 live births results in a baby with Down syndrome, the most frequent cause of mental retardation. As well as being developmentally delayed, persons with Down syndrome begin to lose brain cells in their 30s and inevitably develop Alzheimer's disease in their 40s or 50s.

Holtzman and colleagues William C. Mobley, M.D., Ph.D., and Charles J. Epstein, M.D., from the University of California, San Francisco, analyzed a mouse bred by Muriel Davisson, Ph.D., at the Jackson Laboratory in Bar Harbor, Maine. The mouse has an extra copy of the end of chromosome 16. This chromosome is analogous to human chromosome 21, which is present three times instead of twice in persons with Down syndrome. The duplicated mouse region includes more than 100 genes, including those associated with the syndrome.

The only other animal model of Down syndrome has three complete copies of chromosome 16. "Unfortunately, those mice die at birth," Holtzman says. "Having a model that lives into old age is a huge advantage."

The researchers tracked both cognitive development and anatomical changes in the brain as the mice developed into adults. Like persons with Down syndrome, the mice developed more slowly than normal. Pups took twice as long to find their mothers from the other side of a cage, for example. And adult mice were unable to learn the whereabouts of an underwater platform. "These mice are severely abnormal with regard to their ability to learn new spatial information," Holtzman says.

The researchers also examined the basal forebrain, whose neurons secrete a chemical messenger called acetylcholine. The basal forebrain is one of the areas that loses neurons in Alzheimer's disease.

Pups had a normal quota of neurons in the basal forebrain. But by middle age, this region had lost 30 percent of its acetylcholine-secreting neurons. By old age, there was a 40 percent loss. These

types of neurons did not disappear from regions of the brain that are not affected by Alzheimer's disease, however.

The researchers also observed that cells called astrocytes were enlarged in the hippocampal region of the brain in the Down syndrome mice. "It is felt that astrocytes react when neurons are dying," Holtzman says. "So this observation suggests that the neurons in the hippocampus were not doing well."

The researchers found that two genes in the duplicated part of chromosome 16 - the gene for superoxide dismutase and the gene for amyloid precursor protein - were overexpressed, as they are in persons with Down syndrome. The gene for apoE, which is implicated in Alzheimer's disease, was overexpressed also, even though it does not reside on chromosome 16. "It is possible that this region contains a gene that regulates apoE production," Holtzman says.

Unlike Alzheimer patients, the mice did not develop beta-amyloid plaques in the brain. "So in Down syndrome, the development of beta-amyloid plaques may involve more than simple overexpression of amyloid precursor protein. And Alzheimer's disease may be much more complicated than deposition in the brain of beta-amyloid," Holtzman says. "All we really know is that Alzheimer's disease involves neuronal dysfunction and loss that is associated with a characteristic pathology. With these mice, we may be able to study some of the other factors that contribute to neuron degeneration in this disorder."

Grants from the National Institute on Aging and the American Federation for Aging Research supported this study.