Brain inflammation underlies a large number of neurodegenerative diseases as well as normal aging. The cyclooxygenases COX-1 and COX-2 catalyze the first committed step in prostaglandin synthesis, and the inducible isoform COX-2 promotes neuronal injury in several models, including cerebral ischemia, epilepsy, and neurodegenerative conditions such as Parkinson's disease and ALS. In addition, epidemiologic studies suggest that NSAIDs, which inhibit COX activity, may serve a preventive function in the development of AD. However, the utility of COX inhibitors, and in particular COX-2 inhibitors, is limited because production of beneficial prostaglandins may be blocked, leading to untoward side effects. Thus, it is important to identify specific downstream prostaglandin pathways that promote neuronal injury to understand how COX-2 mediates neuronal damage. Prostaglandins are lipid signaling molecules that activate a class of G-protein coupled receptors that are expressed on different cell types in brain and can have diverse effects on cAMP production, phosphoinositol turnover, and intracellular Ca2+ homeostasis. In recent studies, we have identified a central function of PGE2 signaling through its EP2 receptor in mediating inflammation, oxidative stress, and neurotoxicity. PGE2 signaling through the EP2 receptor promotes inflammatory oxidative stress in the LPS model of innate immunity and a model of amyloid deposition. The goal of this proposal is to identify the mechanism(s) by which the PGE2 EP2 receptor is pro-inflammatory and neurotoxic and identify downstream pathways regulated by the EP2 receptor that contribute to neuronal injury in age-related neurodegeneration where inflammation is a key component. We will use both genetic and pharmacological tools in vitro and in vivo. Identification of the downstream mechanisms by which PGE2 signaling through the EP2 receptor promotes secondary neurotoxicity may lead to novel therapeutic strategies in neurodegenerative diseases and age-related cognitive decline.

Public Health Relevance

Cyclooxygenase activity and downstream production of prostaglandins are emerging as critical mediators of neuronal injury in many models of neurological disease, including acute stroke, Parkinson's disease, amyotrophic lateral sclerosis, and Alzheimer's disease (AD). The mechanistic studies outlined in this proposal will identify toxic mechanisms by which a major PGE2 signaling pathway promotes inflammation and neurodegeneration in a model of AD. Our findings will be relevant to the development of novel therapeutic strategies targeting pro- inflammatory pathways in AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG030209-05
Application #
8528258
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Petanceska, Suzana
Project Start
2009-09-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$300,391
Indirect Cost
$116,044
Name
Stanford University
Department
Neurology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Woodling, Nathaniel S; Wang, Qian; Priyam, Prachi G et al. (2014) Suppression of Alzheimer-associated inflammation by microglial prostaglandin-E2 EP4 receptor signaling. J Neurosci 34:5882-94
Johansson, Jenny U; Pradhan, Suraj; Lokteva, Ludmila A et al. (2013) Suppression of inflammation with conditional deletion of the prostaglandin E2 EP2 receptor in macrophages and brain microglia. J Neurosci 33:16016-32
Pradhan, Suraj; Andreasson, Katrin (2013) Commentary: Progressive inflammation as a contributing factor to early development of Parkinson's disease. Exp Neurol 241:148-55
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