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

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.