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2012 Grants - Green
Role of Microglia in Alzheimer's and in Abeta and Tau Immunotherapy
Kim Green, Ph.D.
University of California, Irvine
2012 New Investigator Research Grant
Two key hallmarks of the Alzheimer's brain are plaques (or clumps) that contain the protein fragment beta-amyloid and tangles that contain abnormal tau protein. Plaques and tangles damage cell-to-cell communication in the brain and can promote brain cell death. Both formations also activate the body's immune system. Immune cells called microglia travel to and surround amyloid plaques, causing the brain to become inflamed. Current research, however, suggests that microglia may also help eliminate beta-amyloid from the brain. Yet the mechanisms by which this removal process occurs have not been determined.
In preliminary experiments, Kim Green, Ph.D., and colleagues have been studying the actions of proteins called colony stimulating factor 1 receptor (CSF1R) antagonists. Receptor antagonists bind to, but do not trigger a receptor. Experiments with Alzheimer's-like mice have shown that these proteins completely clear microglia from the brain. Thus the researchers now have an effective tool for clarifying the role that microglia play in structural and functional changes related to Alzheimer's.
For this project, Dr. Green and colleagues will examine how microglia are involved in the development of plaques and tangles, and how they may help the immune system combat those protein aggregates. First, they will engineer a strain of mouse that develops robust amyloid plaques and brain inflammation. They will then treat some of the mice with CSF1R antagonists to determine how the loss of microglia affects plaque formation and cognition in the animals. In the second part of the study, Alzheimer's-like mice will receive both CSF1R antagonists and antibodies for either beta-amyloid or tau. The team will then assess how the loss of microglia affects immunotherapy treatments designed to eliminate plaques or tangles. Results of these experiments could reveal how microglia combat Alzheimer's-related structural and functional changes before they form—and how they might help clear those changes after formation. Such knowledge could lead to more effective dementia therapies.