Modulation of amyloid-ß peptide-induced toxicity through inhibition of JNK nuclear localization and caspase-2 activation.
J Alzheimers Dis
; 22(2): 557-68, 2010.
Article
en En
| MEDLINE
| ID: mdl-20847398
ABSTRACT
Amyloid-ß (Aß) 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 Aß-induced apoptosis. Here, we investigated stress signaling events triggered by soluble Aß and further explored alternative pathways of neuroprotection by TUDCA in differentiated rat neuronal-like PC12 cells. Morphologic evaluation of apoptosis confirmed that Aß-induced nuclear fragmentation was prevented by TUDCA. In addition, Aß 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 Aß-induced apoptosis. Furthermore, active caspase-2 cleaved golgin-160 and was localized to the Golgi complex. Importantly, TUDCA abrogated Aß-induced JNK/caspase-2 signaling. In conclusion, we show that JNK is the proximal stress sensor for soluble Aß-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 Aß apoptotic signaling through the Golgi complex. These data provide new information linking apoptotic properties of Aß 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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Transducción de Señal
/
Péptidos beta-Amiloides
/
Apoptosis
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Proteínas Quinasas JNK Activadas por Mitógenos
/
Caspasa 2
Límite:
Animals
Idioma:
En
Revista:
J Alzheimers Dis
Asunto de la revista:
GERIATRIA
/
NEUROLOGIA
Año:
2010
Tipo del documento:
Article
País de afiliación:
Portugal