Caspase-3 activation by beta-amyloid and prion protein peptides is independent from their neurotoxic effect.
Synthetic peptides corresponding to residues 25-35 of beta-amyloid (beta 25-35) and 106-126 of prion protein (PrP 106-126) are amyloidogenic and cause neuronal death by apoptosis in vitro. We evaluated, in rat cortical neurons, the role of caspases activation in the peptides neurotoxicity by measuring of caspase-3 (CPP32) activity and applying a non-selective caspase inhibitor (z-VAD-fmk) or CPP32-specific inhibitor (Asp-Glu-Val-Asp-CHO (DEVD-CHO)). CPP32 was dose-dependently activated by both peptides (2.5-50 microM). The caspase inhibitors completely abolished the CPP32 activation induced by the peptides. However, the neurotoxic effect was partially attenuated with z-VAD-fmk, while no antagonism was found with DEVD-CHO. Thus, although beta 25-35 and PrP 106-126 robustly activated CPP32, their neurotoxic effect was independent of this caspase activation.
Sáez-Valero
J
J
Biology of Neurodegenerative Disorders, Istituto di Ricerche Farmacologiche 'Mario Negri Via Eritrea 62, 20157, Milan, Italy.
Angeretti
N
N
Forloni
G
G
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology* / Q000633:toxicity; D011328:Prions / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats
D000590:Amino Acid Chloromethyl Ketones; D016229:Amyloid beta-Peptides; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D010446:Peptide Fragments; D011328:Prions; C074636:amyloid beta-protein (25-35); C108637:aspartyl-glutamyl-valyl-aspartal; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C082632:prion protein (106-126); C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases