Yuekui Li, M.D., Ph.D.
University of Arkansas for Medical Sciences
Little Rock, Arkansas

2003 New Investigator Research Grant

Postmortem study of brain tissue shows that inflammation is a key pathological process at work in the Alzheimer brain, and epidemiological studies suggest that individuals taking anti-inflammatory drugs to treat such conditions as arthritis have a reduced risk of Alzheimer’s disease. However, clinical trials specifically designed to test whether anti-inflammatory drugs may benefit Alzheimer’s have so far been disappointing. But the strength of evidence that inflammation plays a critical role has convinced many experts that gaining a clearer understanding of the process will lead to new treatments or preventions.

In this project, the researchers will study the exact sequence of chemical events set in motion when beta-amyloid activates microglia, specialized brain cells that support nerve cells and play a role in the brain’s immune response. Beta-amyloid is the protein fragment that aggregates into the plaques that are a hallmark Alzheimer brain abnormality. The research team believes that exposure to beta-amyloid may stimulate microglia to release cytokines, inflammatory molecules that can damage and, ultimately, kill nerve cells. Death of the nerve cells triggers release of more beta-amyloid as well as its parent molecule APP, which normally is embedded in the outer fatty membrane of healthy nerve cells. The research team will produce laboratory cultures of nerve cells and microglia to study the exact mechanisms at work in this vicious cycle, with special focus on how activation of microglia disrupts the internal structure of nerve cells and destroys cell-to-cell connections that form the basis of learning, memory, and information processing. Insights gained may suggest new therapeutic strategies for suppressing inflammation or reveal other promising targets for intervention.