title: DNA damage-inducing agents elicit gamma-secretase activation mediated by 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.
authors.affiliation: Department of Biochemistry and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: S M
authors.initials: SM
authors.lastname: Jin
authors.forename: H J
authors.initials: HJ
authors.lastname: Cho
authors.forename: E S
authors.initials: ES
authors.lastname: Jung
authors.forename: M-Y
authors.initials: MY
authors.lastname: Shim
authors.forename: I
authors.initials: I
authors.lastname: Mook-Jung
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D016466:CHO Cells; D002166:Camptothecin / Q000633:toxicity; D006224:Cricetinae; D003412:Cricetulus; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage; D004789:Enzyme Activation; D005047:Etoposide / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors; D000083162:Mitochondrial Permeability Transition Pore; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D017382:Reactive Oxygen Species; D005047:Etoposide; D045304:Cytochromes c; D053829:Amyloid Precursor Protein Secretases; D005978:Glutathione; D002166:Camptothecin