Research Summary: A team from the University of Texas Medical Branch at Galveston, including BrightFocus-supported scientist and senior author, Kelly Dineley, Ph.D., tested the effects of a FDA-approved diabetes drug, called rosiglitazone, on mice engineered to have a form of Alzheimer's disease. The team monitored the treated mice for changes in cognitive abilities and analyzed the changes to protein activities in the brain. They found that the drug improved the learning and memory abilities of these mice. In particular, they determined that the drug was making these improvements through a protein called PPAR gamma, which apparently dampens the negative effects caused by a disease-induced increase in the activity of another protein, called ERK.
Significance: Diabetes and poor control of blood sugar have been connected with an increased risk for Alzheimer's disease (for a recent example, see the June 28, 2012, News Update concerning BrightFocus-supported researcher, Kristine Yaffe, M.D.) Dr. Dineley and collaborators have brought us one step closer to understanding the specific mechanisms and proteins—namely, ERK and PPAR gamma signaling—that are behind this connection. Therefore, the team has identified potential targets for future treatments of Alzheimer's disease. In addition, the results of this groundbreaking research lend hope to the ongoing clinical trials that are testing whether already-FDA-approved diabetes drugs can alter biochemical disease biomarkers and/or prevent cognitive decline in individuals with Alzheimer's (including the BrightFocus-supported clinical trial by Stephen Arnold, M.D.)
An FDA-approved drug initially used to treat insulin resistance in diabetics has shown promise as a way to improve cognitive performance in some people with Alzheimer's disease.
Working with genetically engineered mice designed to serve as models for Alzheimer's, University of Texas Medical Branch at Galveston researchers found that treatment with the anti-insulin-resistance drug rosiglitazone enhanced learning and memory as well as normalized insulin resistance. The scientists believe that the drug produced the response by reducing the negative influence of Alzheimer's on the behavior of a key brain-signaling molecule.
The molecule, called extracellular signal-regulated kinase (ERK), becomes hyperactive both in the brains of Alzheimer's patients and in the mice at a disease stage corresponding to mild cognitive impairment in human Alzheimer's. This excessive activity leads to improper synaptic transmission between neurons, interfering with learning and memory. Rosiglitazone brings ERK back into line by activating what's known as the peroxisome proliferator-activated receptor gamma (PPARγ) pathway, which interacts with genes that respond to both PPARγ and ERK.
“Using this drug appears to restore the neuronal signaling required for proper cognitive function,” said UTMB professor Larry Denner, the lead author of a paper describing this work now online (posted Nov. 21) in the Journal of Neuroscience. “It gives us an opportunity to test several FDA-approved drugs to normalize insulin resistance in Alzheimer's patients and possibly also enhance memory, and it also gives us a remarkable tool to use in animal models to understand the molecular mechanisms that underlie cognitive issues in Alzheimer's.”
ERK dysfunction in the Alzheimer's mouse model was discovered several years ago by UTMB associate professor Kelly Dineley, senior author of the Journal of Neuroscience paper. But putting together the protein, gene and memory pieces of the puzzle required a multidisciplinary translational research team including animal cognitive neuroscientists, biochemists, molecular biologists, mass spectrometrists, statisticians and bioinformaticists.
“We were extraordinarily lucky to have this diverse group of experts right here on our campus at UTMB that could coalesce to bring such different ways of thinking to bear on a common problem,” Denner said. “It was quite a challenge to get all of these experts communicating in a common scientific language. But now that we have this team working, we can move on to even more detailed and difficult questions.”
Now the UTMB research team and other investigators across the world are starting clinical trials to investigate the value of therapies for insulin resistance in early-stage Alzheimer's disease in humans.
This research was supported by the National Institutes of Health, the BrightFocus Foundation, the Sealy Foundation for Biomedical Research, the Emmett and Miriam McCoy Foundation, the Cullen Trust for Health Care and Jerry and Winkie Mohn.
Adapted from the University of Texas Medical Branch at Galveston
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