Alzheimer's Disease (AD) is characterized by neurodegeneration associated with deposition of beta amyloid (Abeta) plaques. This induces an inflammatory response marked by infiltration of microglial cells and astrocytes and leads to neuronal dysfunction and cell death in regions of the brain with cholinergic/purinergic innervation. These brain cell types express G protein-coupled P2Y receptors for extracellular nucleotides that regulate cellular responses known to be altered by Abeta in AD, although the ability of Abeta to modulate P2Y receptor functions has not been investigated. Proposed studies will investigate a P2Y2 receptor subtype that has been shown to be up-regulated in response to tissue damage and can mediate cellular responses typically associated with cell proliferation and inflammation, physiological endpoints of significant relevance to the AD phenotype. We will investigate the effects of factors implicated in the progression of AD on various functions regulated by P2Y2 receptors in neuronal and glial cells from regions of the brain that are most relevant to AD. Specifically, we will determine the signal transduction pathways coupled to P2Y2 nucleotide receptors in glial and neuronal cells using a variety cells using a variety of pharmacological and molecular biological nucleotide receptors in glial and neuronal cells using a variety of pharmacological and molecular biological approaches. In close collaboration with Projects 1 and 3 (PIs, G, Sun and G. Wood), we will determine whether Abeta and oxidized human brain-like lipoproteins (oxHB-LP) affect signal transduction pathways, inducible gene expression, and oxidized human brain-like lipoproteins (oxHB-LP) affect signal transduction pathways, inducible gene expression, and prostanoid release associated with P2Y2 receptors in glial and neuronal cells. Finally, our preliminary studies suggest that the P2Y2 receptor, by virtue of an Arg-Gly-Asp sequence in its first extracellular loop, interacts with the vitronectin receptor alphavbeta3, an integrin known to regulate inflammatory responses, cell proliferation and cell motility. In this project, we will determine whether P2Y2 receptor interactions with alphavbeta3 play a role in mitogenesis, inflammation and cell motility. The proposed studies will provide new information about the role of P2Y nucleotide receptors in AD and aid in the development of novel pharmacotherapies for preventing neurodegeneration of brain tissue due to glial cell activation and infiltration, and decreased functionality of neuronal cells.
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