Researchers at the University of South Florida’s (USF) Roskamp Institute have isolated a new brain receptor that, when targeted, may help to prevent the adverse immune response that some say leads to Alzheimer’s disease.

The team’s data and conclusions have appeared in a series of reports, including the December 17, 1999, issue of Science, the September 7 Journal of Biological Chemistry, and the October 15 Journal of Neuroscience.

Led by Michael Mullan, M.D., Ph.D., a professor of psychiatry and director of the Roskamp Institute and the University of South Florida Memory Disorders Clinic, the USF team has focused on the link between neuronal degeneration and the activation of the immune response in the brain, which occurs early in the development of Alzheimer’s.

Previous research had shown that the immune response plays a critical role in Alzheimer’s disease. The immune response, which results in brain inflammation, is mediated by microglia, support cells in the brain.

The researchers reported in last year’s Science article that a signaling mechanism in the brain, known as the CD40 receptor-CD40 ligand interaction, when triggered in the brain of an Alzheimer’s patient, causes the microglia to release cytokines, including tumor necrosis factor—alpha and interleukin 1-beta, proteins that are cytotoxic and mediate the inflammatory response. It is the microglial-induced inflammation that leads to damage to and eventually the death of neurons. Beta-amyloid, the protein that makes up the plaques associated with Alzheimer’s, has been shown to be a trigger for the CD40 receptor-CD40 ligand interaction, thereby activating the inflammatory response.

It was this and similar research that had previously led to clinical trials of known ant-inflammatory medications in the treatment of Alzheimer’s. However, several drugs, including aspirin, ibuprofen, and other nonsteroidal anti-inflammatory drugs (NSAIDs) in general only showed modest effects in retarding the advance of Alzheimer’s. Trials of steroid anti-inflammatory medications also failed to live up to researchers’ expectations.

In the Journal of Biological Chemistry and Journal of Neuroscience articles, the team delineated the isolation of the previously unknown CD45 receptor, a protein—tryosine phosphatase—in the cell membrane of the microglia. Previous research had isolated the CD45 receptor on the cell surface of T and B lymphocytes circulating through the blood. CD45 had been shown to play a critical role in preventing the activation of these white blood cells, which upon activation lead to inflammation in the peripheral tissues.

The isolation of CD45 in brain microglia and the USF team’s verification that it also inhibits inflammation in the brain are significant in that CD45 is found in the frontal cortex and hippocampus of normal aging individuals. In individuals with Alzheimer’s, the expression of the CD45 receptor on the surface of microglia in these brain regions is markedly increased.

The USF team believes that these results provide substantial evidence that the brain’s immune response is critically involved in the pathological processes of Alzheimer’s, perhaps even earlier than the actual development of inflammation.

"Once brain inflammation occurs," said Terrence Town, a graduate student of Mullan’s at USF and coauthor of the last two studies, "it is probably too late for treatment."

"The next step," said Mullan, "is to apply these findings to new treatment strategies for Alzheimer’s disease. We are now working with the pharmaceutical industry to screen for drugs that will target the brain’s immune cells."