beta-Amyloid (1-40)-induced apoptosis of cultured cortical neurones involves calpain-mediated cleavage of poly-ADP-ribose polymerase.
beta-Amyloid((1-40))-induced apoptosis of cultured cortical neurones involves calpain-mediated cleavage of poly-ADP-ribose polymerase. beta-Amyloid protein is thought to contribute to the pathophysiology of Alzheimer's disease by inducing neuronal apoptosis. Our previous work has demonstrated that beta-amyloid activates voltage-dependent Ca(2+) channels in the cortex, resulting in an increase in intracellular Ca(2+) concentration. Calpain is a Ca(2+)-dependent neutral protease which becomes activated following alterations in intracellular Ca(2+) homeostasis. In this study we have demonstrated that beta-amyloid increases calpain activity in cultured cortical neurones in a time-dependent manner. Use of the cell-permeable calpain inhibitor, MDL 28170, has identified cleavage of the DNA-repair enzyme, poly-ADP-ribose polymerase, and DNA fragmentation as downstream consequences of calpain activation. Thus, we propose that the stimulatory effect of beta-amyloid on Ca(2+) influx triggers calpain-mediated DNA fragmentation in cultured cortical neurones.
Boland
Barry
B
Department of Physiology, Trinity College, Dublin 2, Ireland.
Campbell
Veronica
V
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002154:Calpain / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology; D004347:Drug Interactions; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D010446:Peptide Fragments / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D016229:Amyloid beta-Peptides; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D011065:Poly(ADP-ribose) Polymerases; D002154:Calpain; C058076:calpain inhibitor III