Investigating the role of prostaglandin E2 mediated neuroinflammation in models of neurodegeneration
Abstract/Contents
- Abstract
- Parkinson's Disease (PD) pathophysiology is primarily characterized by the accumulation of misfolded protein aggregates of alpha-synuclein and degeneration of neurons throughout the CNS, in particular the dopaminergic (DA) neurons in the substantia nigra pars compacta. The mechanisms driving these processes, however, remain poorly understood. Recent studies have identified non cell-autonomous mechanisms such as inflammation and oxidative stress as major contributors to disease pathology in various neurodegenerative diseases including PD. Neurotoxicity in PD patients and animal models of PD is accompanied by significant increases in microgliosis and astrocytosis. Reactive microglia and astrocytes influence the local tissue environment by secreting inflammatory factors such as cytokines, chemokines, and reactive oxygen and nitrogen species. These inflammatory mediators have been suggested to promote the aggregation of alpha-synuclein in vitro and result in secondary neurotoxicity to DA neurons in vivo. Consistent with these observations, inhibiting inflammation is neuroprotective in animal models of Parkinsonism and may exert preventive effects in human PD. Previous data from our lab and others have shown that different prostaglandin E2 (PGE2) receptors amplify or dampen microglial inflammation in a disease setting. In this dissertation I investigated the contribution of PGE2 mediated inflammatory processes to neurodegeneration in mouse models of Parkinsonism. I focused on two receptors, the EP2 and EP4 receptor, which are expressed in neurons, astrocytes, and microglia. To probe the role of EP2 and EP4 in an inflammatory context, I stimulated microglia with oligomeric alpha-synuclein in vitro and injected mice with the neurotoxin MPTP in vivo. I used receptor agonists and antagonists to inhibit or activate the EP receptors and utilized the Cre-loxP genetic strategy to conditionally knock-out the receptors from specific cell types in the brain. My results show that PGE2 promotes neuroinflammation through the microglial EP2 receptor, and conversely suppresses it through the microglial EP4 receptor. Specifically, activating microglial EP2 increases the production of pro-inflammatory factors in vitro, and deleting microglial EP2 reduces MPTP associated microgliosis and astrocytosis in vivo. On the other hand, activating microglial EP4 suppresses the secretion of pro-inflammatory cytokines, chemokines, and ROS in vitro, and deleting microglial EP4 enhances MPTP associated microgliosis, astrocytosis, and infiltration of T-cells in vivo. Furthermore, systemically treating animals with an EP4 receptor agonist exerts a neuroprotective effect in the MPTP model. These results suggest that EP receptors may be potential therapeutic drug-targets for the treatment of PD and associated neurodegenerative diseases. My work shows that PGE2 is a critical inflammatory signaling molecule that plays a context-dependent and cell-specific role in neurodegeneration. My results support the hypothesis that the EP2 receptor plays a pro-inflammatory role while the EP4 receptor plays an anti-inflammatory and neuroprotective role in models of Parkinsonism. Understanding the contribution of PGE2 to the progression of Parkinsonian pathology has given us novel insights into the mechanisms of neuroinflammation and neurodegeneration.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2014 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Pradhan, Suraj |
|---|---|
| Associated with | Stanford University, Neurosciences Program. |
| Primary advisor | Andreasson, Katrin |
| Primary advisor | Ricci, Anthony |
| Thesis advisor | Andreasson, Katrin |
| Thesis advisor | Ricci, Anthony |
| Thesis advisor | Brunet, Anne, 1972- |
| Thesis advisor | Steinman, Lawrence |
| Thesis advisor | Wyss-Coray, Anton |
| Advisor | Brunet, Anne, 1972- |
| Advisor | Steinman, Lawrence |
| Advisor | Wyss-Coray, Anton |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Suraj Pradhan. |
|---|---|
| Note | Submitted to the Program in Neurosciences. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2014. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2014 by Suraj Sunil Pradhan
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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