Modulation of Amyloid-beta Peptide-Induced Toxicity through Inhibition of JNK Nuclear Localization and Caspase-2 Activation

Amyloid-beta (A beta) peptide-induced neurotoxicity is typically associated with apoptosis. In previous studies, we have shown that tauroursodeoxycholic acid (TUDCA), an endogenous anti-apoptotic bile acid, modulates A beta-induced apoptosis. Here, we investigated stress signaling events triggered by soluble A beta and further explored alternative pathways of neuroprotection by TUDCA in differentiated rat neuronal-like PC12 cells. Morphologic evaluation of apoptosis confirmed that A beta-induced nuclear fragmentation was prevented by TUDCA. In addition, A beta exposure resulted in activation of the early stress c-Jun N-terminal kinase (JNK) pathway, JNK nuclear translocation, and caspase-2 activation. Knock-down experiments of JNK established caspase-2 as a specific downstream target of JNK in A beta-induced apoptosis. Furthermore, active caspase-2 cleaved golgin-160 and was localized to the Golgi complex. Importantly, TUDCA abrogated A beta-induced JNK/caspase-2 signaling. In conclusion, we show that JNK is the proximal stress sensor for soluble A beta-induced toxicity, which translocates to the nucleus, activates caspase-2, and is strongly modulated by TUDCA in PC12 neuronal cells. Active caspase-2 cleaves golgin-160, suggesting caspase-2-dependent transduction of A beta apoptotic signaling through the Golgi complex. These data provide new information linking apoptotic properties of A beta peptide to distinct subcellular mechanisms of toxicity. Further characterization of this signaling pathway and exact targets of modulation are likely to provide new perspectives for modulation of amyloid-induced apoptosis by TUDCA.