p38-targeted compounds hold promise for Alzheimer's disease treatment

Linda J. Van Eldik, director of the University of Kentucky Sanders-Brown Center on Aging, has been awarded a $750,000 grant to further her research into a possible treatment for Alzheimer's disease. The grant is from the Edward N. And Della L. Thome Memorial Foundation, and was one of only eight Awards in Alzheimer's Disease Drug Discovery Research to be given in the U.S. in 2010.

Van Eldik's research project focuses on developing an orally active, small molecule drug to inhibit the protein kinase known as p38alphaMAPK. The protein stimulates overproduction of detrimental inflammatory molecules in the brain called proinflammatory cytokines. In normal brain activity, inflammatory and anti-inflammatory molecules operate together to keep brain functions in balance. In the brains of people who have Alzheimer's disease, this balance appears to be disrupted and the overproduction of proinflammatory cytokines leads to poor neuron function, and eventually symptoms of dementia.

Because inflammatory and anti-inflammatory molecules both serve important roles in normal brain function, it is not possible to treat Alzheimer's disease by turning off all inflammatory molecules in the brain. Rather, a successful compound must selectively target proteins like p38alphaMAPK that drive the disruptive inflammatory responses. Van Eldik's goal is to develop a selective small molecule drug to act on this culprit kinase to suppress overactive production of pro-inflammatory cytokines.

Successful so far in an animal model of Alzheimer's disease, Van Eldik's p38-targeted compounds have promise. The grant from the Thome Foundation will enable her to refine the best compound for possible use as a drug. Research will continue in cellular and animal models, as Van Eldik and her collaborators work to identify an optimal candidate drug for future clinical development and testing in humans.