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2011 Grants - Wesson
The Biological Basis of Phenotypic Diversity of Microglia in AD
Daniel Wesson, Ph.D.
Case Western Reserve University
2011 Multi-Centered Project Grant-Component Project
Note: This is one part of a multi-part description. For an introduction to some of the concepts mentioned here, please read the document Lamb and Colleagues Overview.
Microglia are a type of mononuclear phagocyte (MNP; see Overview) found only in the brain. Under normal conditions, they are usually in a resting, inactivated state. When a microglial cell encounters a foreign object, such as a bacterial protein, it becomes activated, setting in motion various mechanisms to respond to potential disease-causing agents. In recent years, scientists have discovered that microglia have at least two activated states, denoted as M1 and M2.
One of the molecules that causes activation of microglia in the brain is amyloid plaque, one of the hallmarks of Alzheimer's pathology. Amyloid plaque consists of aggregates of the protein fragment beta-amyloid. The consequences of amyloid-induced activation of microglia are not well understood.
Daniel Wesson, Ph.D. and colleagues have proposed to study the activation of microglia by amyloid and the effects of such activation on brain inflammation. Using genetic engineering techniques, the researchers will inhibit the signals that cause activation of microglia when the cells encounter amyloid. They will then examine how inhibition of this signal affects activation of the microglia to the M1 or M2 state, as well as the effects on inflammation and deposition of new amyloid plaque during disease progression.
Dr. Wesson's team also plans to examine the role of another type of MNP found in the blood, monocytes. When stimulated, these cells travel to the brain and are indistinguishable from microglia. Dr. Wesson and colleagues have overcome this problem by developing a mouse model in which monocytes express a protein that can be visualized with a fluorescent light. Using this model system, the researchers will investigate the role of monocytes in brain inflammation during the development of Alzheimer-like pathology. These studies will help to define the different roles of microglia and monocytes during disease progression, and may help to define potential strategies to reduce brain inflammation.