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Abeta25-35 alters Akt activity, resulting in Bad translocation and mitochondrial dysfunction in cerebrovascular endothelial cells.
J Cereb Blood Flow Metab 2005; 25(11):1445-55JC

Abstract

The amyloid-beta peptide (Abeta) induces apoptosis in cerebrovascular endothelial cells (CECs), contributing to the pathogenesis of cerebral amyloid angiopathy. We have previously shown that Abeta induces apoptosis in CECs. In the present study, we report that Abeta25-35-induced CEC apoptosis involves the inactivation of Akt, a signaling kinase important in maintaining cell viability. Akt prevents the activation of death-signaling events by facilitating the inactivation of proapoptotic proteins such as Bad. We applied three strategies to show that Abeta25-35 inactivation of Akt is causally related to Abeta25-35-induced CEC death by preventing Bad activation and subsequent mitochondrial dysfunction (reflected by the release of endonuclease G and Smac, two proapoptotic intermembranous proteins of the mitochondria). Wortmannin, a PI3-kinase inhibitor, enhanced Abeta25-35-induced Bad activation, mitochondrial dysfunction and CEC death. Enhancement of Akt activity by a Tat-Akt fusion protein, or by viral gene transfer of a constitutively active mutant of akt, reduced Bad activation, mitochondrial dysfunction, and CEC death. Using a siRNA strategy to knock down the bad gene, we showed that Bad activation is causally related to Abeta25-35-induced mitochondrial dysfunction and CEC death. Together, these results establish that the Akt-Bad cascade is altered by Abeta25-35, resulting in CEC apoptosis.

Authors+Show Affiliations

Department of Neurology, Washington University School of Medicine, St Louis, Missouri 63110, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

15973355

Citation

Yin, Ke-Jie, et al. "Abeta25-35 Alters Akt Activity, Resulting in Bad Translocation and Mitochondrial Dysfunction in Cerebrovascular Endothelial Cells." Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism, vol. 25, no. 11, 2005, pp. 1445-55.
Yin KJ, Lee JM, Chen H, et al. Abeta25-35 alters Akt activity, resulting in Bad translocation and mitochondrial dysfunction in cerebrovascular endothelial cells. J Cereb Blood Flow Metab. 2005;25(11):1445-55.
Yin, K. J., Lee, J. M., Chen, H., Xu, J., & Hsu, C. Y. (2005). Abeta25-35 alters Akt activity, resulting in Bad translocation and mitochondrial dysfunction in cerebrovascular endothelial cells. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism, 25(11), pp. 1445-55.
Yin KJ, et al. Abeta25-35 Alters Akt Activity, Resulting in Bad Translocation and Mitochondrial Dysfunction in Cerebrovascular Endothelial Cells. J Cereb Blood Flow Metab. 2005;25(11):1445-55. PubMed PMID: 15973355.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Abeta25-35 alters Akt activity, resulting in Bad translocation and mitochondrial dysfunction in cerebrovascular endothelial cells. AU - Yin,Ke-Jie, AU - Lee,Jin-Moo, AU - Chen,Hong, AU - Xu,Jan, AU - Hsu,Chung Y, PY - 2005/6/24/pubmed PY - 2005/12/13/medline PY - 2005/6/24/entrez SP - 1445 EP - 55 JF - Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism JO - J. Cereb. Blood Flow Metab. VL - 25 IS - 11 N2 - The amyloid-beta peptide (Abeta) induces apoptosis in cerebrovascular endothelial cells (CECs), contributing to the pathogenesis of cerebral amyloid angiopathy. We have previously shown that Abeta induces apoptosis in CECs. In the present study, we report that Abeta25-35-induced CEC apoptosis involves the inactivation of Akt, a signaling kinase important in maintaining cell viability. Akt prevents the activation of death-signaling events by facilitating the inactivation of proapoptotic proteins such as Bad. We applied three strategies to show that Abeta25-35 inactivation of Akt is causally related to Abeta25-35-induced CEC death by preventing Bad activation and subsequent mitochondrial dysfunction (reflected by the release of endonuclease G and Smac, two proapoptotic intermembranous proteins of the mitochondria). Wortmannin, a PI3-kinase inhibitor, enhanced Abeta25-35-induced Bad activation, mitochondrial dysfunction and CEC death. Enhancement of Akt activity by a Tat-Akt fusion protein, or by viral gene transfer of a constitutively active mutant of akt, reduced Bad activation, mitochondrial dysfunction, and CEC death. Using a siRNA strategy to knock down the bad gene, we showed that Bad activation is causally related to Abeta25-35-induced mitochondrial dysfunction and CEC death. Together, these results establish that the Akt-Bad cascade is altered by Abeta25-35, resulting in CEC apoptosis. SN - 0271-678X UR - https://www.unboundmedicine.com/medline/citation/15973355/Abeta25_35_alters_Akt_activity_resulting_in_Bad_translocation_and_mitochondrial_dysfunction_in_cerebrovascular_endothelial_cells_ L2 - http://journals.sagepub.com/doi/full/10.1038/sj.jcbfm.9600139?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -