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The Journal of Neuroscience, February 22, 2006, 26(8):2290-2299; doi:10.1523/JNEUROSCI.5103-05.2006
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Neurobiology of Disease
Protein Phosphatase 2A Regulates bim Expression via the Akt/FKHRL1 Signaling Pathway in Amyloid- Peptide-Induced Cerebrovascular Endothelial Cell Death
Ke-Jie Yin,1
Chung Y. Hsu,1,2
Xiao-Yan Hu,1
Hong Chen,1
Sha-Wei Chen,1
Jan Xu,1 and
Jin-Moo Lee1
1Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110, and 2Taipei Medical University, Taipei 110, Taiwan
Correspondence should be addressed to Dr. Jin-Moo Lee, Department of Neurology, Campus Box 8111, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. Email: leejm{at}neuro.wustl.edu
Amyloid- peptide (A)-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 A-induced cerebrovascular degeneration in vivo. A similar expression profile was observed in A-treated CECs. Furthermore, A 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 A before bim expression. FKHRL1 activity was negatively regulated by phosphorylation catalyzed by Akt, an anti-apoptotic kinase. Akt upregulation by adenoviral gene transfer inhibited A-induced FKHRL1 activation and bim induction. In addition, A 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 A-induced Akt inactivation and FKHRL1 activation, leading to an attenuation of bim expression and cell death in CECs. Coimmunoprecipitation experiments revealed that A enhanced the binding of the PP2A regulatory subunit PP2AC to Akt. These results implicate PP2A as an early regulator of A-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.
Key words: amyloid ; peptide; apoptosis; bim; ceramide-activated protein phosphatases; cerebral endothelial cells; FKHRL1
Received Aug. 15, 2005;
accepted Dec. 22, 2005.
Correspondence should be addressed to Dr. Jin-Moo Lee, Department of Neurology, Campus Box 8111, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. Email: leejm{at}neuro.wustl.edu
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