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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

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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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