Microglial activation is a prominent feature of numerous neuropathologies including Alzheimer's disease, multiple sclerosis and stroke. As the tissue macrophage of the CNS, microglia have the potential to regulate and be regulated by cells of the CNS and by CNS-infiltrating immune cells. The exquisite sensitivity of microglia to these signals, coupled with their ability to develop a broad range of effector functions allows the CNS to tailor microglial function for specific physiological needs. As yet the mechanisms by which the CNS and the immune system regulate microglial function are incompletely defined. We have recently discovered that subsets of microglia in the healthy murine CNS constitutively express Triggering Receptors Expressed on Myeloid cells-2 (TREM-2), illustrating microglial heterogeneity not only between brain regions, but also even within a single brain region. While microglial expression of TREM-2 is repressed by LPS, expression was dramatically upregulated in transgenic mice overexpressing beta-amyloid but only in those cells immediately surrounding amyloid plaques. Conversely, while unactivated microglia do not express TREM-1, LPS-activated microglia do. Functionally, these receptors have the potential to regulate critical states of microglial activation and differentiation in potentially opposing directions. Our preliminary studies suggest microglia express additional and perhaps CNS-specific forms of these receptors. Some of these forms may have the potential to serve as "decoy" receptors for the as yet unknown ligand(s) for these receptors. Here we propose 1) to clone, identify and generate antisera specific for each form, in order to characterize TREM expression in healthy and inflamed CNS; 2) dissect the potential intracellular signaling pathways triggered by these receptors; and 3) define the functional consequences of TREM expression by microglia. Our analysis will focus on signals and outcomes relevant for bacterial signals, CNS autoimmunity, and Alzheimer's disease.

R01NS045735

2003-04-01

2008-02-28