CCAAT/enhancer-binding protein delta/miR135a/thrombospondin 1 axis mediates PGE2-induced angiogenesis in Alzheimer's disease.

Abstract

In Alzheimer's disease (AD), large populations of endothelial cells undergo angiogenesis due to brain hypoxia and inflammation. Substantial evidence from epidemiologic, pathologic, and clinical reports suggests that vascular factors are critical for the pathogenesis of AD. However, the precise mechanistic correlation between inflammation and angiogenesis in AD has not been well elucidated. Prostaglandin E2 (PGE2), a key factor of the inflammatory response, has been known to promote angiogenesis. In this study, we demonstrated that PGE2 acts through EP4 receptor and protein kinase A to modulate CCAAT/enhancer-binding protein delta (CEBPD) abundance in astrocytes. Attenuated vessel formation was observed in the brains of AppTg/Cebpd(-/-) mice. We showed that miR135a was responsive to the induction of CEBPD and further negatively regulated thrombospondin 1 (THBS1) transcription by directly targeting its 3'-untranslated region (3'UTR) in astrocytes. Furthermore, conditioned media from astrocytes expressing miR135a promoted Human umbilical vein endothelial cells (HUVECs) tube-like formation, which correlated with the effects of PGE2 on angiogenesis. Our results indicated that CEBPD contributes to the repression of THBS1 transcription by activating the expression of miR135a in astrocytes following PGE2 treatment. We provided new evidence that astrocytic CEBPD increases angiogenesis during AD pathogenesis. This discovery supports the negative influence of CEBPD activation in astrocytes with respect to AD pathogenesis and implies that the CEBPD/miR135a/THBS1 axis could be a therapeutic target of AD.

• Authors: Chiung-Yuan Ko, Yu-Yi Chu, Shuh Narumiya, Jhih-Ying Chi, Tomoyuki Furuyashiki, Tomohiro Aoki, Shao-Ming Wang, Wen-Chang Chang, Ju-Ming Wang
• Journal: Neurobiology of aging (Neurobiol Aging) Vol. 36 Issue 3 Pg. 1356-68 (Mar 2015) ISSN: 1558-1497 [Electronic] United States
• PMID: 25554493 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• MicroRNAs
• Thrombospondin 1
• CCAAT-Enhancer-Binding Protein-delta
• Dinoprostone

Topics

• Alzheimer Disease (genetics, pathology)
• Animals
• Astrocytes (metabolism, pathology)
• CCAAT-Enhancer-Binding Protein-delta (physiology)
• Cells, Cultured
• Dinoprostone (physiology)
• Mice, Inbred C57BL
• Mice, Transgenic
• MicroRNAs (physiology)
• Molecular Targeted Therapy
• Neovascularization, Pathologic (genetics, pathology)
• Thrombospondin 1 (physiology)