Abstract

EXCEED THE SPACE PROVIDED. Alzheimer's disease (AD) already is a serious public health problem and looms as a potential public health disaster as coming generations achieve longer average life spans. Numerous experiments and epidemiologic studies point to products of cyclooxygenase (COX) and lipid peroxidation as potential contributors to processes that initiate AD. Of the many potential products generated by these pathways, we have shown that both brain prostaglandin 2 (PGE2), a product of COX, and p2-isoprostanes (IsoPs), products of lipid peroxidation, are elevated early hi the course of AD; both compounds activate eicosanoid receptors, thus establishing them as potential therapeutic targets. The long-range goals of this project are to determine the mechanisms by which PGE2 and F2-IsoPs contribute to the neuronal oxidative damage that is characteristic of AD. We will test the hypothesis that activation of specific PGE2 receptor subtypes in brain can enhance or suppress neuronal oxidative damage, and that specific F2-IsoPs enter into a reinforcing cycle by further stimulating production of PGE2 via activation of cell surface receptors.
The specific aims are: (1) to determine the PGE2 receptor subtypes that enhance or suppress cerebral oxidative damage in vivo using a mouse model of AD pathogenesis, (2) to determine the specific PGE2 receptor subtypes that enhance or suppress Ap42- activated migroglial-mediated oxidative damage and neurodegeneration, (3) to determine receptor-mediated mechanisms by which F2-IsoPs stimulate PGE2 production in neurons and glia, and thereby reinforce the processes investigated in Specific Aims 1 and 2. Successful completion of these experiments will further pur knowledge of the mechanisms that underlie neurodegeneration and identify novel therapeutic targets to suppress oxidativedamage to brain in AD and perhaps other neurodegenerative diseases. PERFORMANCE SITE ========================================Section End===========================================

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG024011-03
Application #
6933871
Study Section
Special Emphasis Panel (ZAG1-ZIJ-9 (J2))
Program Officer
Snyder, Stephen D
Project Start
2003-09-16
Project End
2008-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
3
Fiscal Year
2005
Total Cost
$435,550
Indirect Cost

  Institution

Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195

  Publications

Latimer, Caitlin S; Flanagan, Margaret E; Cimino, Patrick J et al. (2017) Neuropathological Comparison of Adult Onset and Juvenile Huntington's Disease with Cerebellar Atrophy: A Report of a Father and Son. J Huntingtons Dis 6:337-348
Yang, Yue; Shiao, Christine; Hemingway, Jake Frederick et al. (2013) Suppressed retinal degeneration in aged wild type and APPswe/PS1ýýE9 mice by bone marrow transplantation. PLoS One 8:e64246
Shi, Ju; Wang, Qian; Johansson, Jenny U et al. (2012) Inflammatory prostaglandin E2 signaling in a mouse model of Alzheimer disease. Ann Neurol 72:788-98
Montine, Thomas J; Sonnen, Joshua A; Milne, Ginger et al. (2010) Elevated ratio of urinary metabolites of thromboxane and prostacyclin is associated with adverse cardiovascular events in ADAPT. PLoS One 5:e9340
Shi, Ju; Johansson, Jenny; Woodling, Nathaniel S et al. (2010) The prostaglandin E2 E-prostanoid 4 receptor exerts anti-inflammatory effects in brain innate immunity. J Immunol 184:7207-18
Keene, C Dirk; Chang, Rubens C; Lopez-Yglesias, Americo H et al. (2010) Suppressed accumulation of cerebral amyloid {beta} peptides in aged transgenic Alzheimer's disease mice by transplantation with wild-type or prostaglandin E2 receptor subtype 2-null bone marrow. Am J Pathol 177:346-54
Keene, C Dirk; Chang, Rubens; Stephen, Christina et al. (2009) Protection of hippocampal neurogenesis from toll-like receptor 4-dependent innate immune activation by ablation of prostaglandin E2 receptor subtype EP1 or EP2. Am J Pathol 174:2300-9
Cimino, Patrick J; Sokal, Izabela; Leverenz, James et al. (2009) DOCK2 is a microglial specific regulator of central nervous system innate immunity found in normal and Alzheimer's disease brain. Am J Pathol 175:1622-30
Liang, Xibin; Wang, Qian; Shi, Ju et al. (2008) The prostaglandin E2 EP2 receptor accelerates disease progression and inflammation in a model of amyotrophic lateral sclerosis. Ann Neurol 64:304-14
Sonnen, Joshua A; Montine, Kathleen S; Quinn, Joseph F et al. (2008) Biomarkers for cognitive impairment and dementia in elderly people. Lancet Neurol 7:704-14

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