title: 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.affiliation: Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chiung-Yuan
authors.initials: CY
authors.lastname: Ko
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yu-Yi
authors.initials: YY
authors.lastname: Chu
authors.affiliation: Core Research for Evolutional Science and Technology (CREST), Kyoto, Japan.
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan.
authors.forename: Jhih-Ying
authors.initials: JY
authors.lastname: Chi
authors.affiliation: Core Research for Evolutional Science and Technology (CREST), Kyoto, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Furuyashiki
authors.affiliation: Core Research for Evolutional Science and Technology (CREST), Kyoto, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Aoki
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University, Tainan.
authors.forename: Shao-Ming
authors.initials: SM
authors.lastname: Wang
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wen-Chang
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University, Tainan, Taiwan; Institute of Basic Medical Sciences, National Cheng Kung University, Tainan; Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Infectious Disease and Signaling Research Center, National Cheng Kung University, Tainan, Taiwan. Electronic address: yumingw@mail.ncku.edu.tw.
authors.forename: Ju-Ming
authors.initials: JM
authors.lastname: Wang
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000502:physiology*; D002478:Cells, Cultured; D015232:Dinoprostone / Q000502:physiology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000502:physiology*; D058990:Molecular Targeted Therapy; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology*; D019700:Thrombospondin 1 / Q000502:physiology*
chemical_list: D035683:MicroRNAs; D019700:Thrombospondin 1; D051743:CCAAT-Enhancer-Binding Protein-delta; D015232:Dinoprostone
keywords: Alzheimer's disease; Angiogenesis; CEBPD; PGE2; miRNA