Neuroprotective properties of Bcl‐w in Alzheimer disease

Zhu, Xiongwei; Yang, Wei; Ogawa, Osamu; Lee, Hyoung Gon; Raina, Arun K.; Siedlak, Sandra L.; Harris, Peggy L.R.; Fujioka, Hisashi; Shimohama, Shun; Tabaton, Massimo; Atwood, Craig S.; Petersen, Robert B.; Perry, George; Smith, Mark A.

doi:10.1111/j.1471-4159.2004.02416.x

Cited by 46 publications

(36 citation statements)

References 46 publications

(82 reference statements)

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“…Significance is defined as **p Ͻ 0.01 in comparison to A␤ [25][26][27][28][29][30][31][32][33][34][35]Control. 2003), the neural function of Bcl-w includes increasing resistance to neuronal apoptosis. A protective role of Bcl-w is also supported by recent findings by Zhu et al (2004) in both Alzheimer brain tissue and cell culture. Consistent with these observations, our data show that A␤-induced neuronal death was reduced by overexpression of Bcl-w and potentiated by suppression of Bcl-w. Paired with our observation that toxic levels of A␤ greatly deplete Bcl-w levels before the onset of cell death, these data strongly suggest an important role of Bcl-w in the mechanism of A␤-induced neuronal apoptosis.…”

Section: Discussionsupporting

confidence: 66%

“…Previous studies examining the role of the Bcl-2 family in A␤-induced apoptosis have observed that A␤ can significantly decrease expression of antiapoptotic Bcl-2 and Bcl-x L (Forloni et al, 1996;Paradis et al, 1996;Wei et al, 2000;Tamagno et al, 2003) and increase expression of proapoptotic Bax and Bim (Paradis et al, 1996;Yin et al, 2002;Tamagno et al, 2003). Curiously, subtoxic and mildly toxic levels of A␤ can increase expression of the antiapoptotic Bcl-w (Zhu et al, 2004), perhaps suggesting induction of a protective response under certain stress conditions. In the current study, we observed modest effects of neurotoxic levels of A␤ on Bcl-2, bax, and bim expression.…”

Section: Discussionmentioning

confidence: 96%

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

Yao

Nguyen²,

Pike³

2005

J. Neurosci.

199

139

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␤-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.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 96%

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

Yao

Nguyen²,

Pike³

2005

J. Neurosci.

199

139

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“…39 Although the role of Bcl2l2 in cardiomyocytes remains unclear, it is thought to play an important protective role in neurons and in the diseased brain. 40 Because the expressions of Bid, Bok, and Mcl1 changed in a similar way between WT mice and CHOP-deficient mice, they may not contribute to the differences in cardiac dysfunction between WT mice and CHOP-deficient mice. These findings suggest that ER stress initiates CHOP-dependent apoptotic signaling, which finally leads to activation of mitochondria-dependent apoptotic signaling via several Bcl2 family members and contributes to heart failure induced by pressure overload.…”

Section: Discussionmentioning

confidence: 99%

Ablation of C/EBP Homologous Protein Attenuates Endoplasmic Reticulum–Mediated Apoptosis and Cardiac Dysfunction Induced by Pressure Overload

et al. 2010

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Background-Apoptosis may contribute to the development of heart failure, but the role of apoptotic signaling initiated by the endoplasmic reticulum in this condition has not been well clarified. Methods and Results-In myocardial samples from patients with heart failure, quantitative real-time polymerase chain reaction revealed an increase in messenger RNA for C/EBP homologous protein (CHOP), a transcriptional factor that mediates endoplasmic reticulum-initiated apoptotic cell death. We performed transverse aortic constriction or sham operation on wild-type (WT) and CHOP-deficient mice. The CHOP-deficient mice showed less cardiac hypertrophy, fibrosis, and cardiac dysfunction compared with WT mice at 4 weeks after transverse aortic constriction, although the contractility of isolated cardiomyocytes from CHOP-deficient mice was not significantly different from that in the WT mice. In the hearts of CHOP-deficient mice, phosphorylation of eukaryotic translation initiation factor 2␣, which may reduce protein translation, was enhanced compared with WT mice. In the hearts of WT mice, CHOP-increased apoptotic cell death with activation of caspase-3 was observed at 4 weeks after transverse aortic constriction. In contrast, CHOP-deficient mice had less apoptotic cell death and lower caspase-3 activation at 4 weeks after transverse aortic constriction. Furthermore, the Bcl2/Bax ratio was decreased in WT mice, whereas this change was significantly blunted in CHOP-deficient mice. Real-time polymerase chain reaction microarray analysis revealed that CHOP could regulate several Bcl2 family members in failing hearts. Conclusions-We propose the novel concept that CHOP, which may modify protein translation and mediate endoplasmic reticulum-initiated apoptotic cell death, contributes to development of cardiac hypertrophy and failure induced by pressure overload. (Circulation. 2010;122:361-369.)

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“…Human neuroblastoma M17 cells were grown as described before (36). Transfection was performed using Effectene (Qiagen) (20) and 300 g/ml geneticin (Invitrogen) or 400 g/ml of hygromycin B (Calbiochem) was included in the medium for stable cell line selection.…”

Section: Methodsmentioning

confidence: 99%

Amyloid-β overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins

Wang

Siedlak

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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750

608

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Mitochondrial dysfunction is a prominent feature of Alzheimer disease but the underlying mechanism is unclear. In this study, we investigated the effect of amyloid precursor protein (APP) and amyloid ␤ on mitochondrial dynamics in neurons. Confocal and electron microscopic analysis demonstrated that Ϸ40% M17 cells overexpressing WT APP (APPwt M17 cells) and more than 80% M17 cells overexpressing APPswe mutant (APPswe M17 cells) displayed alterations in mitochondrial morphology and distribution. Specifically, mitochondria exhibited a fragmented structure and an abnormal distribution accumulating around the perinuclear area. These mitochondrial changes were abolished by treatment with ␤-site APP-cleaving enzyme inhibitor IV. From a functional perspective, APP overexpression affected mitochondria at multiple levels, including elevating reactive oxygen species levels, decreasing mitochondrial membrane potential, and reducing ATP production, and also caused neuronal dysfunction such as differentiation deficiency upon retinoic acid treatment. At the molecular level, levels of dynamin-like protein 1 and OPA1 were significantly decreased whereas levels of Fis1 were significantly increased in APPwt and APPswe M17 cells. Notably, overexpression of dynamin-like protein 1 in these cells rescued the abnormal mitochondrial distribution and differentiation deficiency, but failed to rescue mitochondrial fragmentation and functional parameters, whereas overexpression of OPA1 rescued mitochondrial fragmentation and functional parameters, but failed to restore normal mitochondrial distribution. Overexpression of APP or A␤-derived diffusible ligand treatment also led to mitochondrial fragmentation and reduced mitochondrial coverage in neuronal processes in differentiated primary hippocampal neurons. Based on these data, we concluded that APP, through amyloid ␤ production, causes an imbalance of mitochondrial fission/fusion that results in mitochondrial fragmentation and abnormal distribution, which contributes to mitochondrial and neuronal dysfunction.amyloid precursor protein ͉ DLP1 ͉ mitochondrial fragmentation ͉ OPA1 ͉ perinuclear accumulation

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Neuroprotective properties of Bcl‐w in Alzheimer disease

Cited by 46 publications

References 46 publications

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

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

Ablation of C/EBP Homologous Protein Attenuates Endoplasmic Reticulum–Mediated Apoptosis and Cardiac Dysfunction Induced by Pressure Overload

Amyloid-β overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins

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