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.

Apoptosis and insulin resistance in liver and peripheral tissues of morbidly obese patients is associated with different stages of non-alcoholic fatty liver disease

“…In fact, a connection between liver JNK, caspase-2 and apoptosis is an attractive hypothesis, as it was recently shown that caspase-2-and JNK-mediated signalling is one of the mechanisms involved in age-related muscle cell apoptosis [46]. Curiously, our team very recently demonstrated that caspase-2 is a specific key downstream target of JNK in amyloid β-induced apoptosis [47]. However, the role of different JNK isoforms in different human insulin target tissues remains to be explored.…”

DNA damage‐induced apoptosis and mitogen‐activated protein kinase pathway contribute to the toxicity of dronedarone in hepatic cells

“…6F). It is known that the specific JNK inhibitor SP600125 was found to partially inhibit caspase-2 activation (Dirsch et al, 2004;Viana et al, 2010). Therefore, our findings suggest that the activation of caspase-2 and JNK/p38 pathways interact with each other in response to dronedarone exposure.…”

The inhibitory effects of bile acids on catalytic and non-catalytic functions of acetylcholinesterase as a therapeutic target in Alzheimer’s disease

“…It was also previously reported that endogenous bile acids are potent anti-apoptotic agents in neuronal cells that are exposed to Aβ (Viana et al, 2010). They are further known as powerful neuroprotective agents in various neurodegenerative diseases.…”

“…This group can pass through the blood brain barrier (BBB) and was also shown to protect neuronal cells against oxidative damage (Lo et al, 2013). The neuroprotective mechanisms of bile acids are not completely understood but prior studies suggest that bile acid derivatives could potentially block the apoptosis process through stabilization of the mitochondrial membrane potential (Δψ m ) and regulation of gene expression (Viana et al, 2010;Ackerman and Gerhard, 2016). Therefore, the main goal of this study was to evaluate the effects of cholic acid (CA) and sodium deoxycholate (SDC), as main bile acids, on the catalytic and non-catalytic functions of AChE.…”