Caspase-2 mediates neuronal cell death induced by beta-amyloid.
beta-amyloid (Abeta) has been proposed to play a role in the pathogenesis of Alzheimer's disease (AD). Deposits of insoluble Abeta are found in the brains of patients with AD and are one of the pathological hallmarks of the disease. It has been proposed that Abeta induces death by oxidative stress, possibly through the generation of peroxynitrite from superoxide and nitric oxide. In our current study, treatment with nitric oxide generators protected against Abeta-induced death, whereas inhibition of nitric oxide synthase afforded no protection, suggesting that formation of peroxynitrite is not critical for Abeta-mediated death. Previous studies have shown that aggregated Abeta can induce caspase-dependent apoptosis in cultured neurons. In all of the neuronal populations studied here (hippocampal neurons, sympathetic neurons, and PC12 cells), cell death was blocked by the broad spectrum caspase inhibitor N-benzyloxycarbonyl-val-ala-asp-fluoromethyl ketone and more specifically by the downregulation of caspase-2 with antisense oligonucleotides. In contrast, downregulation of caspase-1 or caspase-3 did not block Abeta(1-42)-induced death. Neurons from caspase-2 null mice were totally resistant to Abeta(1-42) toxicity, confirming the importance of this caspase in Abeta-induced death. The results indicate that caspase-2 is necessary for Abeta(1-42)-induced apoptosis in vitro.
Troy
C M
CM
Department of Pathology, Taub Institute for the Study of Alzheimer's Disease, New York 10032, USA. cmt2@columbia.edu
Rabacchi
S A
SA
Friedman
W J
WJ
Frappier
T F
TF
Brown
K
K
Shelanski
M L
ML
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053143:Caspase 2; D053148:Caspase 3; D020169:Caspases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008959:Models, Neurological; D009414:Nerve Growth Factors / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D009566:Nitrates / Q000378:metabolism; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D016716:PC12 Cells; D010446:Peptide Fragments / Q000633:toxicity*; D051381:Rats; D013482:Superoxide Dismutase / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000166:cytology / Q000502:physiology
D016229:Amyloid beta-Peptides; D009414:Nerve Growth Factors; D009566:Nitrates; D020319:Oligodeoxyribonucleotides, Antisense; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C039642:peroxynitric acid; D013482:Superoxide Dismutase; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053143:Caspase 2; D053148:Caspase 3; D020169:Caspases