Divergence of the apoptotic pathways induced by 4-hydroxynonenal and amyloid beta-protein.
In this paper, we examine the hypothesis that 4-hydroxynonenal (HNE), a product of lipid peroxidation, is a key mediator of cell death resulting from beta-amyloid exposure. We revisit the effects of HNE on different neuronal cell types to determine which caspase or caspases are required for HNE-induced death, and to compare these results with the known caspase requirements in other death paradigms. We have previously shown that in a given neuronal cell type different death stimuli can evoke stimulus-specific apoptotic pathways. We now show that HNE treatment of neuronal cells induced dose-dependent death and caspase activity which were blocked by inhibition of caspases. Antisense down-regulation of caspases-3, -7 or -9 provided complete protection from HNE-induced death, as did down-regulation of the caspase regulators APAF-1 and DIABLO. Conversely, this work and our previous studies of three other death paradigms show that caspase-3 is not required for death induced by beta-amyloid, SOD1 down-regulation, or trophic factor deprivation. We also show that HNE accumulated in settings where death does not ensue. We conclude that HNE toxicity is mediated via a caspase-9-dependent pathway but that HNE accumulation need not induce cell death nor is it an obligate mediator of Abeta-induced cell death.
Rabacchi
Sylvia A
SA
Department of Pathology, Columbia University College of Physicians and Surgeons, 630 W. 168th Street, New York, NY 10032, USA.
Friedman
Wilma J
WJ
Shelanski
Michael L
ML
Troy
Carol M
CM
D000447:Aldehydes / Q000378:metabolism* / Q000633:toxicity; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D053477:Apoptotic Protease-Activating Factor 1; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D053148:Caspase 3; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051379:Mice; D024101:Mitochondrial Proteins / Q000187:drug effects / Q000378:metabolism; D009414:Nerve Growth Factors / Q000172:deficiency; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016716:PC12 Cells; D011506:Proteins / Q000378:metabolism; D051381:Rats; D013482:Superoxide Dismutase / Q000172:deficiency; D000072105:Superoxide Dismutase-1
D000447:Aldehydes; D016229:Amyloid beta-Peptides; C506593:Apaf1 protein, mouse; C506594:Apaf1 protein, rat; D051017:Apoptosis Regulatory Proteins; D053477:Apoptotic Protease-Activating Factor 1; D002352:Carrier Proteins; D061945:Caspase Inhibitors; C489013:DIABLO protein, rat; C499605:Diablo protein, mouse; D004791:Enzyme Inhibitors; D024101:Mitochondrial Proteins; D009414:Nerve Growth Factors; D011506:Proteins; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; C506434:Casp9 protein, mouse; C506435:Casp9 protein, rat; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; C027576:4-hydroxy-2-nonenal