Olivera M. Mitrasinovic, Ph.D.
Stanford University
Stanford, California

2003 New Investigator Research Grant

Inflammation is a characteristic part of the pathology in the Alzheimer brain. It was also an unwanted side effect of the “Alzheimer vaccine” based on a synthetic form of beta-amyloid, the protein fragment that aggregates into the amyloid plaques that are another hallmark Alzheimer pathology. Previous work has shown that in microglia, specialized brain cells that support nerve cells and play a role in the brain’s immune response, beta-amyloid triggers abundant production of a cell-surface molecule called a macrophage-stimulating colony factor (M-CSF) receptor. Production of M-CSF receptors in turn generates molecules called cytokines associated with inflammation. These events stimulate the microglia to engulf and “digest” beta-amyloid, reducing levels of the fragment but at the cost of creating inflammation.

This project will explore the complicated signaling pathways involved in this biochemical sequence of events in microglia to see if it might be possible to stimulate production of M-CSF receptors and accelerate elimination of beta-amyloid without triggering the intermediate inflammatory step. Using laboratory cultures of microglia and nerve cells, the researchers will study whether inactivating the genes that code production of cytokines reduces inflammation while still increasing engulfment and “digestion” of beta-amyloid. Clearer understanding of these functions in microglia may suggest ways to reduce inflammation by suppressing activity of cytokines, an approach that may offer a novel approach to treatment as well as one strategy for refining the “Alzheimer vaccine.”