After 20 years of research, scientists from the Stanford School of Medicine and the Lucile Packard Children’s Hospital have identified a gene that may be responsible for mental retardation in individuals with Down syndrome. This new research links the over-expression of amyloid precursor protein, known as App, to abnormal neural transport and neural degeneration.

According to the National Down Syndrome Society, 350,000 families in America are affected by Down syndrome. One out of 733 babies is born with the condition, which is caused by an extra copy of the 21st chromosome.

The research team used mouse models of Down syndrome to show that an increased dose of App “acts to markedly decrease NGF [nerve growth factor],” a molecule released by a neuron’s target in a process known as retrograde transport. This causes degeneration of critical neurons, stated the research paper, which was published in the July 6 issue of Neuron.

Neural deterioration is a factor in the cognitive dysfunction that afflicts individuals with Down syndrome, and possibly Alzheimer’s disease as well.

Neurologist William Mobley, a professor in the School of Medicine, is the senior author of the paper. He directs the Lucile Packard Children’s Hospital’s Down Syndrome Center and the University’s Neuroscience Institute.

Mobley described his research team’s task in a telephone interview with The Stanford Weekly.

“We began with the idea that you could quantify very carefully the changes in the brains of these mice with Down syndrome,” he said. “In this really complex mouse, you start with a definite abnormality and try to trace it down to a gene.”

“In this case, we traced it down to an extra copy of this gene. The mouse has an extra chromosome, and so one gene in that extra chromosome seems to make a big difference,” Mobley continued.

Researchers said that this discovery might also be applicable to Alzheimer’s disease, as, according to primary author and senior research scientist Ahmad Salehi, the pathophysiologies of both conditions are similar.

Mobley outlined three ways in which this breakthrough is significant.

“First, this shows we can trace down abnormalities to specific genes,” he said. “It makes clear that this is a real abnormality that fundamentally affects the brain, and we really just have one gene that can make a difference.”

“Second, now that we know the gene, we can now know what the mechanism is and can make other drug targets,” Mobley continued. “And third, App itself is a target. It’s probably the first realistic target that has been found for Down syndrome.”

Salehi discussed how the identification of this gene furthers the understanding of Down syndrome.

The completion of this research, he said, means that “we can break this complex syndrome into sub-phenotypes and relate those to triplication of different genes.”

In addition, the findings emphasize the potential dangers of App over-expression during critical periods of development or aging.

Salehi described the research process as “very collaborative and multidisciplinary,” as the team of six active researchers joined forces with groups across the country to complete the study.

“In addition, many different methods from stereology to real-time PCR to Q-Dots were needed to achieve our goals,” he said.

Salehi discussed the next step for the research team.

“Now that we know what is happening, we have to understand how it is happening,” he said. “A major task for us is to understand the mechanism by which App over-expression leads to decreased NGF transport.”

“The hope is that now we have a target for therapy at least in our mice,” Salehi said, adding that the researchers hope to be able to reduce App levels pharmacologically.

Mobley said that he hoped this research would lead to a better understanding of Down syndrome in humans as well.

“We’d like to push for clinical trials,” he said. “But that’s going to be a while — there’s a lot of work to do between now and then.”

Mobley called the research “tedious and very hard work,” but acknowledged the “terrific” post-doctoral students on the research team, particularly first authors Salehi and Jean-Dominique Delcroix.