TY - JOUR T1 - Protein Phosphatase 2A Regulates <em>bim</em> Expression via the Akt/FKHRL1 Signaling Pathway in Amyloid-β Peptide-Induced Cerebrovascular Endothelial Cell Death JF - The Journal of Neuroscience JO - J. Neurosci. SP - 2290 LP - 2299 DO - 10.1523/JNEUROSCI.5103-05.2006 VL - 26 IS - 8 AU - Ke-Jie Yin AU - Chung Y. Hsu AU - Xiao-Yan Hu AU - Hong Chen AU - Sha-Wei Chen AU - Jan Xu AU - Jin-Moo Lee Y1 - 2006/02/22 UR - http://www.jneurosci.org/content/26/8/2290.abstract 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 PP2ACαβ to 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. ER -