Multiple caspases are involved in beta-amyloid-induced neuronal apoptosis.
beta-amyloid peptide (Abeta) has been implicated in the pathogenesis of Alzheimer disease and has been reported to induce apoptotic death in cell culture. Cysteine proteases, a family of enzymes known as caspases, mediate cell death in many models of apoptosis. Multiple caspases have been implicated in Abeta toxicity; these reports are conflicting. We show that treatment of cerebellar granule cells (CGC) with Abeta25-35 causes apoptosis associated with increased activity of caspases-2, -3 and -6. Selective inhibition of each of these three caspases provides significant protection against Abeta-mediated apoptosis. In contrast, no change in caspase-1 activity was seen after Abeta25-35 application, nor was inhibition of caspase-1 neuroprotective. Similar to CGC, cortical neuronal cultures treated with Abeta25-35 demonstrate increased caspase-3 activity but not caspase-1 activity. Furthermore, significant neuroprotection is elicited by selective inhibition of caspase-3 in cortical neurons administered Abeta25-35, whereas selective caspase-1 inhibition has no effect. Taken together, these findings indicate that multiple executioner caspases may be involved in neuronal apoptosis induced by Abeta.
Allen
J W
JW
Institute for Cognitive and Computational Sciences, Georgetown University, Washington, DC, USA.
Eldadah
B A
BA
Huang
X
X
Knoblach
S M
SM
Faden
A I
AI
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001798:Blood Proteins / Q000494:pharmacology; D020170:Caspase 1 / Q000378:metabolism; D053143:Caspase 2; D053148:Caspase 3; D053178:Caspase 6; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D002540:Cerebral Cortex / Q000166:cytology; D003374:Coumarins / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000201:enzymology; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000633:toxicity*; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000031:analogs & derivatives / Q000494:pharmacology
C112287:Ac-aspartyl-glutamyl-valyl-aspartyl-aminomethylcoumarin; D000590:Amino Acid Chloromethyl Ketones; D016229:Amyloid beta-Peptides; D001798:Blood Proteins; D061945:Caspase Inhibitors; D003374:Coumarins; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D010446:Peptide Fragments; D011480:Protease Inhibitors; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; C074636:amyloid beta-protein (25-35); C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C427308:benzoylcarbonyl-valyl-aspartyl-valyl-alanyl-aspartyl-fluoromethyl ketone; C417985:butyloxycarbonyl-aspartyl-fluoromethyl ketone; C425776:tyrosyl-valyl-alanyl-aspartic acid fluoromethyl ketone; D014108:Tosylphenylalanyl Chloromethyl Ketone; C505410:Casp3 protein, rat; C505518:Casp6 protein, rat; D053143:Caspase 2; D053148:Caspase 3; D053178:Caspase 6; D020169:Caspases; D020170:Caspase 1