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

Chiung Yuan Ko, Yu Yi Chu, Shuh Narumiya, Jhih Ying Chi, Tomoyuki Furuyashiki, Tomohiro Aoki, Shao Ming Wang, Wen Chang Chang, Ju-Ming Wang

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1356-1368
Number of pages13
JournalNeurobiology of Aging
Volume36
Issue number3
DOIs
Publication statusPublished - 2015 Mar 1

Fingerprint

CCAAT-Enhancer-Binding Protein-delta
Thrombospondin 1
Dinoprostone
Alzheimer Disease
Astrocytes
Brain Hypoxia
Human Umbilical Vein Endothelial Cells
3' Untranslated Regions
Encephalitis
Conditioned Culture Medium
Cyclic AMP-Dependent Protein Kinases
Endothelial Cells
Inflammation
Brain

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Ageing
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

Ko, Chiung Yuan ; Chu, Yu Yi ; Narumiya, Shuh ; Chi, Jhih Ying ; Furuyashiki, Tomoyuki ; Aoki, Tomohiro ; Wang, Shao Ming ; Chang, Wen Chang ; Wang, Ju-Ming. / The CCAAT/enhancer-binding protein delta/miR135a/thrombospondin 1 axis mediates PGE2-induced angiogenesis in Alzheimer's disease. In: Neurobiology of Aging. 2015 ; Vol. 36, No. 3. pp. 1356-1368.
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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.",
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The CCAAT/enhancer-binding protein delta/miR135a/thrombospondin 1 axis mediates PGE2-induced angiogenesis in Alzheimer's disease. / Ko, Chiung Yuan; Chu, Yu Yi; Narumiya, Shuh; Chi, Jhih Ying; Furuyashiki, Tomoyuki; Aoki, Tomohiro; Wang, Shao Ming; Chang, Wen Chang; Wang, Ju-Ming.

In: Neurobiology of Aging, Vol. 36, No. 3, 01.03.2015, p. 1356-1368.

Research output: Contribution to journalArticle

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AU - Ko, Chiung Yuan

AU - Chu, Yu Yi

AU - Narumiya, Shuh

AU - Chi, Jhih Ying

AU - Furuyashiki, Tomoyuki

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AU - Wang, Shao Ming

AU - Chang, Wen Chang

AU - Wang, Ju-Ming

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