Parkinson's disease (PD) derives from the confluence of advancing age, inherited susceptibility, and environmental exposures. While the mechanisms involved are not yet clear, inherited abnormalities in alpha- synuclein (SNCA) and exposure to selected toxicants can mimic some of the facets of PD in rodent models. We propose that the point of convergence for these processes is innate immune activation, especially in the substantia nigra, which may have both deleterious and beneficial effects on neuronal survival. The prostaglandin E2 pathway, a major component of activated innate immunity, is effected through a family of four G-protein coupled receptors called EP1 through EP4. We will test the hypothesis that EP receptor subtypes are fundamentally important in determining the balance of neurotrophic vs. neurotoxic effects of innate immune activation. We will test our hypothesis through Specific Aims that use a genetically altered mouse models and potentially relevant toxicant models: MPTP and cytokine cocktails that mimic the central nervous system effects of peripheral endotoxin exposure. This application is responsive to several points in the NIH Blueprint: it is a direct response to the therapeutic imperative for PD, it is highly translational, and it draws on existing NIH-funded resources. When successfully completed, our proposed work will have advanced and refined our knowledge about potentially important new therapeutic targets that complement other ongoing efforts to protect dopaminergic neurons from innate immune activation and to reduce pathologic forms of SNCA in brain.

Public Health Relevance

We and others already have shown in rodent models that activation of innate immune response with increased production of prostaglandin (PG) E2 damages the same dopaminergic neurons that degenerate in Parkinson's disease (PD). In addition, increased generation of PGE2 in diseased regions of brain is a feature of patients with PD. Here we propose to focus on the PGE2 receptors, called EP1 through EP4, with the goal of developing new therapeutic targets for PD. We will test our hypothesis using genetically altered mouse models combined with potentially relevant environmental toxicant models: MPTP and cytokine cocktails that mimic the central nervous system effects of peripheral endotoxin exposure. When successfully completed, our proposed work will have advanced and refined our knowledge about potentially important new therapeutic targets that complement other ongoing efforts to protect dopaminergic neurons from innate immune activation in patients with PD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES016754-05
Application #
8494046
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Lawler, Cindy P
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$337,136
Indirect Cost
$121,023
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Li, Xianwu; Montine, Kathleen S; Keene, C Dirk et al. (2015) Different mechanisms of apolipoprotein E isoform-dependent modulation of prostaglandin E2 production and triggering receptor expressed on myeloid cells 2 (TREM2) expression after innate immune activation of microglia. FASEB J 29:1754-62
Li, Xianwu; Melief, Erica; Postupna, Nadia et al. (2015) Prostaglandin E2 receptor subtype 2 regulation of scavenger receptor CD36 modulates microglial Aβ42 phagocytosis. Am J Pathol 185:230-9
Cudaback, Eiron; Yang, Yue; Montine, Thomas J et al. (2015) APOE genotype-dependent modulation of astrocyte chemokine CCL3 production. Glia 63:51-65
Cudaback, Eiron; Jorstad, Nikolas L; Yang, Yue et al. (2014) Therapeutic implications of the prostaglandin pathway in Alzheimer's disease. Biochem Pharmacol 88:565-72
Li, Xianwu; Rose, Shannon E; Montine, Kathleen S et al. (2013) Antagonism of neuronal prostaglandin E(2) receptor subtype 1 mitigates amyloid ýý neurotoxicity in vitro. J Neuroimmune Pharmacol 8:87-93
Cudaback, Eiron; Li, Xianwu; Yang, Yue et al. (2012) Apolipoprotein C-I is an APOE genotype-dependent suppressor of glial activation. J Neuroinflammation 9:192
Galasko, Douglas R; Peskind, Elaine; Clark, Christopher M et al. (2012) Antioxidants for Alzheimer disease: a randomized clinical trial with cerebrospinal fluid biomarker measures. Arch Neurol 69:836-41
Li, Xianwu; Cudaback, Eiron; Breyer, Richard M et al. (2012) Eicosanoid receptor subtype-mediated opposing regulation of TLR-stimulated expression of astrocyte glial-derived neurotrophic factor. FASEB J 26:3075-83
Li, Xianwu; Cudaback, Eiron; Keene, C Dirk et al. (2011) Suppressed microglial E prostanoid receptor 1 signaling selectively reduces tumor necrosis factor alpha and interleukin 6 secretion from toll-like receptor 3 activation. Glia 59:569-76
Keene, C Dirk; Cudaback, Eiron; Li, Xianwu et al. (2011) Apolipoprotein E isoforms and regulation of the innate immune response in brain of patients with Alzheimer's disease. Curr Opin Neurobiol 21:920-8

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