Protein phosphatase 2A regulates bim expression via the Akt/FKHRL1 signaling pathway in amyloid-β peptide-induced cerebrovascular endothelial cell death

Ke Jie Yin, Chung Y. Hsu, Xiao Yan Hu, Hong Chen, Sha Wei Chen, Jan Xu, Jin Moo Lee

Research output: Contribution to journalArticle

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Abstract

Amyloid-β peptide (Aβ)-induced death in cerebral endothelial cells (CECs) is preceded by mitochondrial dysfunction and signaling events characteristic of apoptosis. Mitochondria-dependent apoptosis engages Bcl-2 family proteins, especially the BH3-only homologues, which play a key role in initiating the apoptotic cascade. Here, we report that the expression of bim, but not other BH3-only members, was selectively increased in cerebral microvessels isolated from 18-month-old APPsw (Tg2576) mice, a model of cerebral amyloid angiopathy (CAA), suggesting a pivotal role for Bim in Aβ-induced cerebrovascular degeneration in vivo. A similar expression profile was observed in Aβ-treated CECs. Furthermore, Aβ induction of bim expression involved a pro-apoptotic transcription factor, FKHRL1. FKHRL1 bound to a consensus sequence in the bim promoter region and was activated by Aβ before bim expression. FKHRL1 activity was negatively regulated by phosphorylation catalyzed by Akt, an anti-apoptotic kinase. Akt upregulation by adenoviral gene transfer inhibited Aβ-induced FKHRL1 activation and bim induction. In addition, Aβ increased the activity of protein phosphatase 2A (PP2A), a ceramide-activated protein phosphatase. Suppression of PP2A activity by RNA interference or a specific inhibitor, okadaic acid, effectively suppressed Aβ-induced Akt inactivation and FKHRL1 activation, leading to an attenuation of bim expression and cell death in CECs. Coimmunoprecipitation experiments revealed that Aβ enhanced the binding of the PP2A regulatory subunit PP2ACαβto Akt. These results implicate PP2A as an early regulator of Aβ-induced bim expression and CEC apoptosis via the Akt/FKHRL1 signaling pathway. We raise the possibility that this pathway may play a role in cerebrovascular degeneration in CAA.

Original languageEnglish
Pages (from-to)2290-2299
Number of pages10
JournalJournal of Neuroscience
Volume26
Issue number8
DOIs
Publication statusPublished - Feb 22 2006

Fingerprint

Protein Phosphatase 2
Amyloid
Cell Death
Endothelial Cells
Cerebral Amyloid Angiopathy
Peptides
Apoptosis
Okadaic Acid
Ceramides
Phosphoprotein Phosphatases
Consensus Sequence
RNA Interference
Microvessels
Genetic Promoter Regions
Carrier Proteins
Mitochondria
Transcription Factors
Phosphotransferases
Up-Regulation
Phosphorylation

Keywords

  • Amyloid β
  • Apoptosis
  • bim
  • Ceramide-activated protein phosphatases
  • Cerebral endothelial cells
  • FKHRL1
  • Peptide

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Protein phosphatase 2A regulates bim expression via the Akt/FKHRL1 signaling pathway in amyloid-β peptide-induced cerebrovascular endothelial cell death. / Yin, Ke Jie; Hsu, Chung Y.; Hu, Xiao Yan; Chen, Hong; Chen, Sha Wei; Xu, Jan; Lee, Jin Moo.

In: Journal of Neuroscience, Vol. 26, No. 8, 22.02.2006, p. 2290-2299.

Research output: Contribution to journalArticle

Yin, Ke Jie ; Hsu, Chung Y. ; Hu, Xiao Yan ; Chen, Hong ; Chen, Sha Wei ; Xu, Jan ; Lee, Jin Moo. / Protein phosphatase 2A regulates bim expression via the Akt/FKHRL1 signaling pathway in amyloid-β peptide-induced cerebrovascular endothelial cell death. In: Journal of Neuroscience. 2006 ; Vol. 26, No. 8. pp. 2290-2299.
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AU - Yin, Ke Jie

AU - Hsu, Chung Y.

AU - Hu, Xiao Yan

AU - Chen, Hong

AU - Chen, Sha Wei

AU - Xu, Jan

AU - Lee, Jin Moo

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N2 - Amyloid-β peptide (Aβ)-induced death in cerebral endothelial cells (CECs) is preceded by mitochondrial dysfunction and signaling events characteristic of apoptosis. Mitochondria-dependent apoptosis engages Bcl-2 family proteins, especially the BH3-only homologues, which play a key role in initiating the apoptotic cascade. Here, we report that the expression of bim, but not other BH3-only members, was selectively increased in cerebral microvessels isolated from 18-month-old APPsw (Tg2576) mice, a model of cerebral amyloid angiopathy (CAA), suggesting a pivotal role for Bim in Aβ-induced cerebrovascular degeneration in vivo. A similar expression profile was observed in Aβ-treated CECs. Furthermore, Aβ induction of bim expression involved a pro-apoptotic transcription factor, FKHRL1. FKHRL1 bound to a consensus sequence in the bim promoter region and was activated by Aβ before bim expression. FKHRL1 activity was negatively regulated by phosphorylation catalyzed by Akt, an anti-apoptotic kinase. Akt upregulation by adenoviral gene transfer inhibited Aβ-induced FKHRL1 activation and bim induction. In addition, Aβ increased the activity of protein phosphatase 2A (PP2A), a ceramide-activated protein phosphatase. Suppression of PP2A activity by RNA interference or a specific inhibitor, okadaic acid, effectively suppressed Aβ-induced Akt inactivation and FKHRL1 activation, leading to an attenuation of bim expression and cell death in CECs. Coimmunoprecipitation experiments revealed that Aβ enhanced the binding of the PP2A regulatory subunit PP2ACαβto Akt. These results implicate PP2A as an early regulator of Aβ-induced bim expression and CEC apoptosis via the Akt/FKHRL1 signaling pathway. We raise the possibility that this pathway may play a role in cerebrovascular degeneration in CAA.

AB - Amyloid-β peptide (Aβ)-induced death in cerebral endothelial cells (CECs) is preceded by mitochondrial dysfunction and signaling events characteristic of apoptosis. Mitochondria-dependent apoptosis engages Bcl-2 family proteins, especially the BH3-only homologues, which play a key role in initiating the apoptotic cascade. Here, we report that the expression of bim, but not other BH3-only members, was selectively increased in cerebral microvessels isolated from 18-month-old APPsw (Tg2576) mice, a model of cerebral amyloid angiopathy (CAA), suggesting a pivotal role for Bim in Aβ-induced cerebrovascular degeneration in vivo. A similar expression profile was observed in Aβ-treated CECs. Furthermore, Aβ induction of bim expression involved a pro-apoptotic transcription factor, FKHRL1. FKHRL1 bound to a consensus sequence in the bim promoter region and was activated by Aβ before bim expression. FKHRL1 activity was negatively regulated by phosphorylation catalyzed by Akt, an anti-apoptotic kinase. Akt upregulation by adenoviral gene transfer inhibited Aβ-induced FKHRL1 activation and bim induction. In addition, Aβ increased the activity of protein phosphatase 2A (PP2A), a ceramide-activated protein phosphatase. Suppression of PP2A activity by RNA interference or a specific inhibitor, okadaic acid, effectively suppressed Aβ-induced Akt inactivation and FKHRL1 activation, leading to an attenuation of bim expression and cell death in CECs. Coimmunoprecipitation experiments revealed that Aβ enhanced the binding of the PP2A regulatory subunit PP2ACαβto Akt. These results implicate PP2A as an early regulator of Aβ-induced bim expression and CEC apoptosis via the Akt/FKHRL1 signaling pathway. We raise the possibility that this pathway may play a role in cerebrovascular degeneration in CAA.

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KW - Ceramide-activated protein phosphatases

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KW - FKHRL1

KW - Peptide

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