Researchers have reduced Alzheimer's symptoms in mice by deleting a single gene in the brain. The findings may allow the development of therapies that are safer and more selective for preventing and treating the disease.
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New target. Mice with EP2 (left) have more brain plaque than those without the gene (right).
CREDIT: X. Liang et al., The Journal of Neuroscience (2005) |
Alzheimer's disease is associated with inflammation and plaque build-up in the brain. Research suggests that nonsteroidal anti-inflammatories (NSAIDs) such as ibuprofen and naproxen can help prevent symptoms in people by inhibiting the cyclooxygenase pathway, which promotes inflammation. The drugs work by blocking two of the pathway's enzymes, COX-1 and COX-2. Unfortunately, the COX enzymes also help maintain stomach lining, and blocking COX-1 throughout the body can lead to gastric ulcers and intestinal bleeding, while blocking COX-2 may cause stroke.
So Katrin Andreasson, a neurologist at Johns Hopkins University in Baltimore, Maryland, and colleagues started looking for a part of the cyclooxygenase pathway that acts specifically on the brain. Earlier work had shown that one component of the pathway called PGE2 binds to a brain receptor known as EP2. PGE2 levels are often found elevated in Alzheimer's patients, suggesting that interplay between PGE2 and EP2 contributes to inflammation and plaques. After co-author Richard Breyer, a biochemist at Vanderbilt University's Ingram Cancer Center in Nashville, Tennessee, knocked out the EP2 receptor in mice, the elderly adults had significantly less inflammation and plaque in their brains compared to aging mice whose EP2 receptors were still intact. Because mice without EP2 suffered no side effects, developing drugs that block EP2 could be a safe and specific way to combat Alzheimer's, the team reports 2 November in Journal of Neuroscience.
"The study is a milestone in the search for new therapeutic targets for Alzheimer's," says Vanderbilt University pharmacologist Oliver Boutaud, an expert on the cyclooxygenase pathway who was not associated with the study. Some questions remain, such as whether blocking the EP2 receptor would still be protective after the onset of the disease. However, we now have a better idea of the role this pathway plays in Alzheimer's disease, Boutaud says.
--MEAGAN WHITE
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