| First Author | Woodling NS | Year | 2014 |
| Journal | J Neurosci | Volume | 34 |
| Issue | 17 | Pages | 5882-94 |
| PubMed ID | 24760848 | Mgi Jnum | J:210613 |
| Mgi Id | MGI:5571527 | Doi | 10.1523/JNEUROSCI.0410-14.2014 |
| Citation | Woodling NS, et al. (2014) Suppression of Alzheimer-associated inflammation by microglial prostaglandin-E2 EP4 receptor signaling. J Neurosci 34(17):5882-94 |
| abstractText | A persistent and nonresolving inflammatory response to accumulating Abeta peptide species is a cardinal feature in the development of Alzheimer's disease (AD). In response to accumulating Abeta peptide species, microglia, the innate immune cells of the brain, generate a toxic inflammatory response that accelerates synaptic and neuronal injury. Many proinflammatory signaling pathways are linked to progression of neurodegeneration. However, endogenous anti-inflammatory pathways capable of suppressing Abeta-induced inflammation represent a relatively unexplored area. Here we report that signaling through the prostaglandin-E2 (PGE2) EP4 receptor potently suppresses microglial inflammatory responses to Abeta42 peptides. In cultured microglial cells, EP4 stimulation attenuated levels of Abeta42-induced inflammatory factors and potentiated phagocytosis of Abeta42. Microarray analysis demonstrated that EP4 stimulation broadly opposed Abeta42-driven gene expression changes in microglia, with enrichment for targets of IRF1, IRF7, and NF-kappaB transcription factors. In vivo, conditional deletion of microglial EP4 in APPSwe-PS1DeltaE9 (APP-PS1) mice conversely increased inflammatory gene expression, oxidative protein modification, and Abeta deposition in brain at early stages of pathology, but not at later stages, suggesting an early anti-inflammatory function of microglial EP4 signaling in the APP-PS1 model. Finally, EP4 receptor levels decreased significantly in human cortex with progression from normal to AD states, suggesting that early loss of this beneficial signaling system in preclinical AD development may contribute to subsequent progression of pathology. |
