Neuronal apoptosis induced by beta-amyloid is mediated by caspase-8.
The Alzheimer disease-associated beta-amyloid peptide has been shown to induce apoptotic neuronal death. In the present study, we test the hypothesis that the apoptotic pathway activated by beta-amyloid is similar to the pathway activated by the Fas/TNFR family of death receptors, which requires caspase-8 activity and adaptor proteins such as FADD. We demonstrate that the selective caspase-8 inhibitor IETD-fmk blocks neuronal death induced by beta-amyloid. Furthermore, using viral-mediated gene delivery, we show that neurons expressing dominant-negative FADD are protected from apoptosis induced by beta-amyloid. Together these results indicate that the apoptotic pathway activated by beta-amyloid requires both caspase-8 activity and FADD. These findings further support the hypothesis that beta-amyloid might initiate apoptosis by cross-linking death receptors of the Fas/TNFR family.
Ivins
K J
KJ
Institute for Brain Aging and Dementia, University of California at Irvine, Irvine, California, 92697-4540, USA.
Thornton
P L
PL
Rohn
T T
TT
Cotman
C W
CW
D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053200:Fas-Associated Death Domain Protein; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D006801:Humans; D008959:Models, Neurological; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000633:toxicity*; D051381:Rats; D015398:Signal Transduction; D019311:Staurosporine / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; C505533:FADD protein, human; C505535:Fadd protein, rat; D053200:Fas-Associated Death Domain Protein; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505528:Casp8 protein, rat; C506435:Casp9 protein, rat; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D019311:Staurosporine