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DNA damage-inducing agents elicit gamma-secretase activation mediated by oxidative stress
Cited 19 time in
Web of Science
Cited 19 time in Scopus
- Authors
- Issue Date
- 2008-04-19
- Publisher
- Nature Publishing Group
- Citation
- Cell Death Differ. 2008; 15(9): 1375-1384
- Keywords
- Amyloid Precursor Protein Secretases/*metabolism ; Amyloid beta-Protein/*metabolism/pharmacology ; Animals ; CHO Cells ; Camptothecin/toxicity ; Cricetinae ; Cricetulus ; Cytochromes c/metabolism ; Enzyme Activation ; Etoposide/toxicity ; Glutathione/metabolism ; Humans ; Mice ; Mitochondria/metabolism ; Mitochondrial Membrane Transport Proteins/antagonists & inhibitors ; Reactive Oxygen Species/metabolism ; Apoptosis ; DNA Damage ; Oxidative Stress
- Abstract
- According to the amyloid cascade hypothesis, Alzheimer's disease is the consequence of neuronal cell death induced by beta-amyloid (Abeta), which accumulates by abnormal clearance or production. On the other hand, recent studies have shown cell death-induced alteration in amyloid precursor protein (APP) processing, suggesting potential mutual interactions between APP processing and cell death. We have shown previously that the cell death caused by DNA damage-inducing agents (DDIAs) facilitated gamma-secretase activity and Abeta generation in a Bax/Bcl-2-dependent, but caspase-independent manner. Here, we attempted to elucidate the downstream mechanism that modulates gamma-secretase activity in DDIA-treated cells. N-acetyl cysteine, a potent antioxidant, attenuated DDIA-induced enhancement of gamma-secretase activity but failed to rescue cell death. Overexpression of heat shock protein 70, which blocks cytochrome c release from mitochondria, also reduced gamma-secretase activity. Moreover, glutathione depletion significantly facilitated gamma-secretase activity and Abeta generation by enhancing the formation of higher molecular weight gamma-secretase complex before signs of cell death developed. Finally, Abeta treatment, a known inducer of oxidative stress, also increased gamma-secretase activity. Taken together, these results indicate that DDIA-induced gamma-secretase activation is dependent on augmented oxidative stress, and that Abeta and gamma-secretase may activate each other. On the basis of these results, we propose a feed-back loop between oxidative stress and Abeta generation mediated by gamma-secretase activation.
- ISSN
- 1350-9047 (Print)
- Language
- English
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