The Gene Expression Profile of Activated Microglia Cells

Donald M. Kuhn, Ph.D.
Wayne State University
NIEHS Grant P30ES06639

Background: There are three types of glial cells that support the central nervous system: astrocytes, oligodendrocytes, and microglia. Glial cells provide protection for neurons in the central nervous system. The main functions of glial cells are to surround neurons and hold them in place, to supply nutrients and oxygen to neurons, to insulate one neuron from another, and to destroy and remove dead neurons.

Microglia are thought to be highly mobile cells that play numerous important roles in protecting the nervous system. They are also thought to play a role in neurodegenerative disorders. Microglia are normally inactive but become activated in response to antigenic stimulation. Once activated, they proliferate and migrate to the site of injury where they bind to antigens. Activated microglia produce numerous cytokines that can be damaging to neuronal cells. The signaling pathways that result in a neuronally protective or destructive microglia are not known.

Advance: To better understand microglial activation, a group of NIEHS-supported scientists at Wayne State University used microarray analysis to analyze the microglial transriptome, the set of all mRNA molecules for a given set of environmental circumstances. Unlike the genome, which is fixed for a given organism, the transcriptome varies depending upon environmental factors present at any point in time. Microglia were activated with either lipopolysaccharide, a neurotoxic protein associated with HIV infection, or dopamine quinone, all of which have been associated with damage to dopamine producing neurons. The analysis demonstrated that genes that were up-regulated are involved with processes such as immune response, inflammation, and cytokine/chemokine activity. Genes that were down-regulated are responsible for microglial migration, decreased adhesion to extracellular matrix, and reduction in the number of receptors that inhibit chemotaxis and inflammation.

Implications: Microglial activation has been linked to numerous neurological conditions including Alzheimer’s disease, amyotropic lateral sclerosis, Creutsfeldt-Jakob disease, and especially those that target the dopamine-producing neurons such as Parkinson’s disease. Therefore the panel of genes differentially regulated by the three microglial activators in these experiments provides a number of possibilities for future studies to search for early biomarkers of neuronal damage associated with activated microglia.

Citation: Thomas DM, Francescutti-Verbeem DM, Kuhn DM. Gene expression profile of activated microglia under conditions associated with dopamine neuronal damage. FASEB J. 2006 Mar;20(3):515-7.