β-Amyloid-Induced Neuronal Apoptosis Involves c-Jun N-Terminal Kinase-Dependent Downregulation of Bcl-w

Abstract

␤-Amyloid protein (A␤) has been implicated as a key molecule in the neurodegenerative cascades of Alzheimer's disease (AD). A␤ directly induces neuronal apoptosis, suggesting an important role of A␤ neurotoxicity in AD neurodegeneration. However, the mechanism(s) of A␤-induced neuronal apoptosis remain incompletely defined. In this study, we report that A␤-induced neuronal death is preceded by selective alterations in expression of the Bcl-2 family of apoptosis-related genes. Specifically, we observe that A␤ significantly reduces expression of antiapoptotic Bcl-w and Bcl-x L , mildly affects expression of bim, Bcl-2, and bax, but does not alter expression of bak, bad, bik, bid, or BNIP3. A␤-induced downregulation of Bcl-w appears to contribute to the mechanism of apoptosis, because A␤-induced neuronal death was significantly increased by Bcl-w suppression but significantly reduced by Bcl-w overexpression. Downstream of Bcl-w, A␤-induced neuronal apoptosis is characterized by mitochondrial release of second mitochondrion-derived activator of caspase (Smac), an important precursor event to cell death. We observed that Smac release was potentiated by suppression of Bcl-w and reduced by overexpression of Bcl-w. Next, we investigated the upstream mediator of A␤-induced Bcl-w downregulation and Smac release. We observed that A␤ rapidly activates c-Jun N-terminal kinase (JNK). Pharmacological inhibition of JNK effectively inhibited all measures of A␤ apoptosis: Bcl-w downregulation, Smac release, and neuronal death. Together, these results suggest that the mechanism of A␤-induced neuronal apoptosis sequentially involves JNK activation, Bcl-w downregulation, and release of mitochondrial Smac, followed by cell death. Complete elucidation of the mechanism of A␤-induced apoptosis promises to accelerate development of neuroprotective interventions for the treatment of AD.

Site-Specific Blockade of RAGE-VdPrevents Amyloid-β Oligomer Neurotoxicity

“…4). Consistent with previous studies (Estus et al, 1997;Yao et al, 2005;Florent et al, 2006;Malaplate-Armand et al, 2006), we found that A␤O-, A␤F-, and A␤A-induced SHSY-5Y cell death involved the activation of apoptotic pathways as revealed by TUNEL and caspase activity assays (Figs. 2-4).…”

Haloperidol induces apoptosis via the σ2 receptor system and Bcl-XS

“…47 In addition, neuronal apoptosis induced by the Ab (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) fragment was recently shown to downregulate the expression of two anti-apoptotic Bcl-2 homologues, namely Bcl-w and Bcl-XL. 48 The synergism we demonstrate between HAL and the Ab(1-40) peptide, which correlates with increased detection of Bcl-XS and of a Bcl-XS-VDAC complex that coincides with an increase in cytosolic cytochrome c, could have serious impact in the clinical setting.…”

Estrogen Regulates Bcl-w and Bim Expression: Role in Protection against β-Amyloid Peptide-Induced Neuronal Death

“…Effect of JNK inhibition on estrogen regulation of Bcl-w and Bim expression JNK signaling is an established signaling pathway in the regulation of Bcl-2 family expression (Harris and Johnson, 2001;Bae and Song, 2003;Yao et al, 2005). To begin investigating the role of JNK signaling in E2 regulation of Bcl-2 family members, we assessed the effect of the specific JNK inhibitor SP600125 (Bennett et al, 2001) on E2 induced bcl-w upregulation and bim downregulation under nonchallenged conditions.…”

“…JNK signaling is linked to transcriptional regulation of many genes (Ip and Davis, 1998), including members of the Bcl-2 family (Harris and Johnson, 2001;Bae and Song, 2003). Interestingly, JNK activation is observed in cultured neurons after A␤ exposure, and its inhibition significantly attenuates A␤ toxicity (Bozyczko-Coyne et al, 2001;Morishima et al, 2001;Troy et al, 2001;Yao et al, 2005). The mitochondrial localization of Bcl-2 proteins suggests that a downstream component of this pathway includes regulation of the proapoptotic molecules released from mitochondria, such as cytochrome c (Liu et al, 1996) and second mitochondrion-derived activator of caspase (Smac/DIABLO) (Du et al, 2000;Verhagen et al, 2000).…”