Chronic inflammation, a major contributor to neurodegeneration in AD, occurs when glial cells (i.e., astrocytes and microglia) undergo prolonged activation in response to oxidative stress. Oxidative stress and neurotoxic oligomeric p-amyloid (Ap) peptide production in AD brain can increase extracellular levels of cytokines and nucleotides that activate receptors in glial cells to stimulate intracellular signaling pathways and promote reactive gliosis, an underlying cause of neuroinflammation. Chronic inflammation can be exacerbated by the infiltration of blood monocytes across the endothelium of cerebral microvessels that maintain the blood-brain barrier. Our research has shown that a G protein-coupled P2Y2 nucleotide receptor (P2Y2R) expressed in astrocytes and vascular cells is activated by the extracellular nucleotides ATP and DTP to induce responses characteristic of reactive gliosis and vascular inflammation. The P2Y2R is distinguished among G protein-coupled receptors in its ability to interact directly with integrins (e.g., avPa/ps) and growth factor receptors to transactivate their signal transduction pathways. Proposed studies will test the hypothesis that chronic inflammation caused by oxidative stress and oligomeric Ap production in AD brain is mediated by P2Y2Rs for cytokine-like nucleotides in astrocytes and cerebromicrovessels through transactivation of integrins and growth factor receptors. P2Y2Rs also activate a-secretase to promote neuroprotective APP processing by distinct pathways from inflammation, suggesting that this divergence in P2Y2R signaling can be exploited to retard the development of AD. Studies will evaluate three specific aims.
Aim 1 will elucidate pro-inflammatory pathways coupled to P2Y2Rs andATP release and the effects of oxidative stress and oligomeric Ap42 in primary astrocytes from TgCRNDS mice that harbor the Swedish (K670M/N671L) and Indiana (V717F) mutations in APP, an accepted animal model of AD, as compared to C57/BL6 (wild type), P2Y2R'/"""""""", and TgCRNDS x P2Y2R~'~ mice. Studies also will determine mechanisms of transcriptional regulation of the P2Y2R.
Aim 2 will determine whether expression of P2Y2Rs, and markers of inflammation and the AD phenotype are up-regulated in astrocytes, neurons and microvessels isolated from brain sections of TgCRNDS mice as compared to C57/BL6, P2Y2R""""""""/"""""""", and TgCRNDS x P2Y2R~'~mice, and quantify ATP release in brain sections.
Aim 3 will determine mechanisms underlying P2Y2R-mediated APP processing in NT-2 cells expressing the Swedish and Indiana double mutant of APP, an in vitro neuronal cell model for AD, and in primary neurons. Together, these studies will provide conclusive evidence to support a role for P2Y2Rs in the pathophysiology of AD, and define novel pathways activated by nucleotides that will lead to better treatments for this debilitating disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
3P01AG018357-10S1
Application #
8530659
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4)
Project Start
Project End
2014-04-30
Budget Start
2011-05-01
Budget End
2013-04-30
Support Year
10
Fiscal Year
2012
Total Cost
$31,028
Indirect Cost
$6,468
Name
University of Missouri-Columbia
Department
Type
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
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