Amyloid-β Peptide-Induced Secretion of Endoplasmic Reticulum Chaperone Glycoprotein GRP94

被引:16
作者
Viana, Ricardo J. S.
Steer, Clifford J. [2 ,3 ]
Rodrigues, Cecilia M. P. [1 ,4 ]
机构
[1] Univ Lisbon, IMedUl, Fac Pharm, Res Inst Med & Pharmaceut Sci, P-1649003 Lisbon, Portugal
[2] Univ Minnesota, Sch Med, Dept Med, Minneapolis, MN 55455 USA
[3] Univ Minnesota, Dept Genet Cell Biol & Dev, Dept Med, Minneapolis, MN 55455 USA
[4] Univ Lisbon, Dept Biochem & Human Biol, P-1649003 Lisbon, Portugal
关键词
Amyloid-beta; ATF-6; alpha; caspase-12; endoplasmic reticulum; GRP94; tauroursodeoxycholic acid; HEAT-SHOCK PROTEINS; CELL-DEATH; ER STRESS; TRANSMEMBRANE PROTEIN; APOPTOTIC PATHWAY; CALCIUM-CHANNELS; NEURONAL DEATH; IN-VIVO; ACTIVATION; GELDANAMYCIN;
D O I
10.3233/JAD-2011-100395
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Amyloid-beta (A beta) peptide-induced neurotoxicity is typically associated with cell death through mechanisms not entirely understood. Here, we investigated stress signaling events triggered by soluble A beta in differentiated rat neuronal-like PC12 cells. Morphologic evaluation of apoptosis confirmed that A beta induced nuclear fragmentation that was prevented by pre-treatment with the antiapoptotic bile acid tauroursodeoxycholic acid (TUDCA). In addition, A beta exposure triggered an early signaling response by the endoplasmic reticulum (ER) and caspase-12-mediated apoptosis, which, however, was independent of the ER-stress pathway. Furthermore, ER stress markers, including GRP94, ATF-6 alpha, CHOP, and eIF2 alpha, were strongly downregulated by A beta, independent of protein degradation, and partially restored by TUDCA. Calpain inhibition prevented caspase-12 activation and reduced levels of ATF-6 alpha. Importantly, A beta-induced GRP94 downregulation was related to protein secretion and partially rescued through inhibition of the secretory pathway by geldanamycin and brefeldin. In conclusion, we showed that the ER is a proximal stress sensor for soluble A beta-induced toxicity, resulting in caspase-12 activation and cell death in PC12 neuronal cells. Moreover, ER chaperone GRP94 secretion was associated with A beta-induced apoptotic signaling. These data provide new information linking apoptotic properties of A beta peptide to distinct subcellular mechanisms of toxicity. Further characterization of this signaling pathway is likely to provide new perspectives for modulation of amyloid-induced apoptosis.
引用
收藏
页码:61 / 73
页数:13
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