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DSRTF Grant Award Recipients Discover a New Potential Therapeutic Strategy to Improve Cognition in Down Syndrome

The Down Syndrome Research and Treatment Foundation (DSRTF) is pleased to announce the publication of an article in Science Translational Medicine on November 18 by DSRTF-supported researchers, Drs. Ahmad Salehi, William Mobley, and colleagues, which describes a new potential therapeutic strategy to address cognitive decline and improve cognition in Down syndrome.
Most people do not have trouble finding, for example, a specific store in a shopping mall, especially if they have been there before.  They are able to integrate input from their senses (such as sight, sound, smell, etc.) with navigational cues from the environment to remember and find their way.  This is called contextual learning.  For people with Down syndrome, contextual learning is much more difficult as they are often unable to correctly integrate sensory and navigational information.  In addition, it is believed that poor contextual learning and memory is involved in additional cognitive decline as people with Down syndrome age. 
This new study by Drs. Salehi, Mobley, and their colleagues at the Stanford University School of Medicine and at the University of California, San Diego (UCSD) School of Medicine explored the basis of contextual learning in a mouse model of Down syndrome and discovered that:
Specific brain cells, or neurons, in one region of the brain are damaged and degenerate leading to the disruption of a specific set of neural circuits;
In contrast, the neurons in another brain region that receive signals from the degenerating neurons remain intact and functional;
One consequence of this specific neuronal degeneration is impairment in contextual learning and memory; and,
Specific drug compounds can essentially restore this important aspect of learning and memory in the mouse model suggesting a new potential therapeutic strategy.
Two regions in the brain, the hippocampus and locus coeruleus (LC), are critical for contextual learning and memory.  Using a mouse model of Down syndrome, the researchers were able to show that these two brain regions were not properly communicating: The LC is damaged, showing degeneration, and therefore does not provide enough of a chemical signal, the neurotransmitter norepinephrine, to the hippocampus. As a consequence, the hippocampus is unable to process sensory and navigational information and contextual learning and memory is impaired.
In addition, Salehi and colleagues showed that by administering two different drug compounds, thereby supplementing the brain of the mouse model of Down syndrome with substitute norepinephrine, contextual learning and memory could be significantly restored.  It is noteworthy that a form of one of these drugs compounds is currently in clinical trials in the U.S. as a potential treatment for a very different condition in humans.
The researchers also demonstrated that the third copy of the App gene in these mice plays a significant role in the degeneration of the LC neurons.  However, removal of this third copy of the App gene did not restore one aspect of contextual learning and memory. It is not yet known to what extent LC neuron degeneration plays a role in contextual learning deficits in humans, but researchers do know that these neurons are also affected in other neurodegenerative diseases such as Alzheimer’s disease.
“These findings in part explain why contextual learning is compromised in people with Down syndrome and offer a potential new therapeutic strategy for improving this cognitive deficit,” said Dr. Salehi. “We found that, despite advanced LC degeneration, we could reverse contextual learning failure in these mice,” added Dr. Mobley. “The possibility is very real that such a therapy, if proven safe, would be effective in treating dementia in later-stage Down syndrome patients.”
“DSRTF is extremely pleased to have provided critical grant funding to advance this important and exciting research,” said Dr. Michael Harpold, Chief Executive Officer of DSRTF. “This new study illustrates DSRTF’s commitment not only to critically needed new discovery research, but also to important translational research to accelerate the advance of new discoveries toward possible clinical trials. Such research is essential for the development of effective new therapies to improve cognition and create new opportunities, including the potential for greater independence and achievement, for all individuals with Down syndrome.”
Since its founding in 2004, DSRTF has generated more than $5.6 million to fund and support major new results-driven research to improve cognition for individuals with Down syndrome.
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