Report on a paper published by Dr. Peter Walter and Dr. Mauro Costa Mattioli in the journal <em>Science</em> about research into memory formation in lab mice commonly used as a model of Down syndrome.
“We started with a situation that looked hopeless, nobody thought anything could be done. But we may have struck gold.” –Peter Walter, PhD.
The cognitive features of Down syndrome (DS) are usually assumed to be “hardwired” and unchangeable, but a recent study suggests that some of them might in fact be more like biochemical “software” that could rewritten through drug treatment.
Using a well-accepted animal model of DS known as the Ts65Dn mouse, researchers in San Francisco and Houston pinpointed changes in protein production in a region of the brain called the hippocampus, which plays a central role in the ability to learn and form long-term memories. Even more exciting, the researchers showed that a drug can reverse the protein changes and improve the mice’s ability to learn.
Normally, humans have two copies of each chromosome, but individuals with DS have a third copy of chromosome 21. Similarly, the Ts65Dn mice have extra copies of corresponding genes. As a result, these mice have many physical, behavioral, and cognitive features similar to DS.
The research team analyzed hippocampus cells in the Ts65Dn mice and found that the cells were making 39 percent less protein than normal. It turns out that cells don’t like having extra genes and react by shutting down protein production, a reaction called integrated stress response,” or ISR. The problem is that for brains to form memories, they need to make proteins.
Is this discovery in mice relevant to humans with DS? Analyzing brain tissue from deceased persons with Down syndrome, the researchers found strong evidence that the ISR is involved in, and perhaps even responsible for, certain DS symptoms.
What’s more, the team identified an enzyme called PKR that is responsible for turning on the ISR in hippocampus cells in DS. Most excitingly, they found a safe, well-studied drug called ISRIB that interferes with the ISR’s ability to shut down protein production. When given to Ts65Dn mice, the drug significantly improved their cognitive function.
The study was published Nov. 14, 2019, in the journal Science. Senior co-authors are Peter Walter, PhD, professor of Biochemistry and Biophysics at University of California San Francisco and Mauro Costa-Mattioli, PhD, a professor of neuroscience at Baylor College of Medicine in Houston, Texas.
Much more research is needed including testing in people with Down syndrome to see if this approach can actually be safe and effective. It will be 5 to 10 years before any drug is FDA approved for this use.
“These findings offer more promise to transform the learning and memory deficits associated with Down syndrome,” said Hampus Hillerstrom, President and CEO of LuMind IDSC Foundation.
Source: LuMind IDSC