title: Modulation of amyloid-β peptide-induced toxicity through inhibition of JNK nuclear localization and caspase-2 activation.
abstract: Amyloid-β (Aβ) 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 Aβ-induced apoptosis. Here, we investigated stress signaling events triggered by soluble Aβ and further explored alternative pathways of neuroprotection by TUDCA in differentiated rat neuronal-like PC12 cells. Morphologic evaluation of apoptosis confirmed that Aβ-induced nuclear fragmentation was prevented by TUDCA. In addition, Aβ 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 Aβ-induced apoptosis. Furthermore, active caspase-2 cleaved golgin-160 and was localized to the Golgi complex. Importantly, TUDCA abrogated Aβ-induced JNK/caspase-2 signaling. In conclusion, we show that JNK is the proximal stress sensor for soluble Aβ-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 Aβ apoptotic signaling through the Golgi complex. These data provide new information linking apoptotic properties of Aβ 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.
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal.
authors.forename: Ricardo J S
authors.initials: RJ
authors.lastname: Viana
authors.forename: Rita M
authors.initials: RM
authors.lastname: Ramalho
authors.forename: Ana F
authors.initials: AF
authors.lastname: Nunes
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Steer
authors.forename: Cecília M P
authors.initials: CM
authors.lastname: Rodrigues
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053143:Caspase 2 / Q000378:metabolism*; D002756:Cholagogues and Choleretics / Q000494:pharmacology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D016716:PC12 Cells / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D002756:Cholagogues and Choleretics; D004791:Enzyme Inhibitors; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D007770:L-Lactate Dehydrogenase; D048031:JNK Mitogen-Activated Protein Kinases; D053143:Caspase 2