title: Amyloid-beta induces Smac release via AP-1/Bim activation in cerebral endothelial cells.
abstract: Insoluble fibrils of amyloid-beta peptide (Abeta) are the major component of senile and vascular plaques found in the brains of Alzheimer's disease (AD) patients. Abeta has been implicated in neuronal and vascular degeneration because of its toxicity to neurons and endothelial cells in vitro; some of these cells die with characteristic features of apoptosis. We used primary cultures of murine cerebral endothelial cells (CECs) to explore the mechanisms involved in Abeta-induced cell death. We report here that Abeta(25-35), a cytotoxic fragment of Abeta, induced translocation of the apoptosis regulator termed second-mitochondria-derived activator of caspase (Smac) from the intramembranous compartment of the mitochondria to the cytosol 24 hr after exposure. In addition, we demonstrated that X chromosome-linked inhibitor-of-apoptosis protein (XIAP) coimmunoprecipitated with Smac, suggesting that the two proteins bound to one another subsequent to the release of Smac from the mitochondria. Abeta(25-35) treatment also led to rapid AP-1 activation and subsequent expression of Bim, a member of the BH3-only family of proapoptotic proteins. Bim knockdown using an antisense oligonucleotide strategy suppressed Abeta(25-35)-induced Smac release and resulted in attenuation of CEC death. Furthermore, AP-1 inhibition, with curcumin or c-fos antisense oligonucleotide, reduced bim expression. These results suggest that Abeta activates an apoptotic cascade involving AP-1 DNA binding, subsequent bim induction, followed by Smac release and binding to XIAP, resulting in CEC death.
authors.affiliation: Department of Neurology and Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Yin
authors.forename: J-M
authors.initials: JM
authors.lastname: Lee
authors.forename: S D
authors.initials: SD
authors.lastname: Chen
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.forename: C Y
authors.initials: CY
authors.lastname: Hsu
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003474:Curcumin / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D024101:Mitochondrial Proteins / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D011233:Precipitin Tests; D011485:Protein Binding / Q000502:physiology; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein
chemical_list: D016229:Amyloid beta-Peptides; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D002352:Carrier Proteins; C499605:Diablo protein, mouse; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D016376:Oligonucleotides, Antisense; D010446:Peptide Fragments; D011506:Proteins; D011518:Proto-Oncogene Proteins; D018808:Transcription Factor AP-1; D051636:X-Linked Inhibitor of Apoptosis Protein; C074636:amyloid beta-protein (25-35); D003474:Curcumin