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Amyloid-beta induces Smac release via AP-1/Bim activation in cerebral endothelial cells.
J Neurosci 2002; 22(22):9764-70JN

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+Show Affiliations

Department of Neurology and Center for the Study of Nervous System Injury, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12427831

Citation

Yin, K J., et al. "Amyloid-beta Induces Smac Release Via AP-1/Bim Activation in Cerebral Endothelial Cells." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 22, no. 22, 2002, pp. 9764-70.
Yin KJ, Lee JM, Chen SD, et al. Amyloid-beta induces Smac release via AP-1/Bim activation in cerebral endothelial cells. J Neurosci. 2002;22(22):9764-70.
Yin, K. J., Lee, J. M., Chen, S. D., Xu, J., & Hsu, C. Y. (2002). Amyloid-beta induces Smac release via AP-1/Bim activation in cerebral endothelial cells. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 22(22), pp. 9764-70.
Yin KJ, et al. Amyloid-beta Induces Smac Release Via AP-1/Bim Activation in Cerebral Endothelial Cells. J Neurosci. 2002 Nov 15;22(22):9764-70. PubMed PMID: 12427831.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Amyloid-beta induces Smac release via AP-1/Bim activation in cerebral endothelial cells. AU - Yin,K J, AU - Lee,J-M, AU - Chen,S D, AU - Xu,J, AU - Hsu,C Y, PY - 2002/11/13/pubmed PY - 2002/11/26/medline PY - 2002/11/13/entrez SP - 9764 EP - 70 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 22 IS - 22 N2 - 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. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/12427831/Amyloid_beta_induces_Smac_release_via_AP_1/Bim_activation_in_cerebral_endothelial_cells_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=12427831 DB - PRIME DP - Unbound Medicine ER -