The role of calcineurin in amyloid-beta-peptides-mediated cell death.
Amyloid beta-peptide (Abeta) is widely held to be associated with Alzheimer's disease. It was previously demonstrated by our group that Abeta induces cell death by an apoptotic process. We report here that activation of the caspase-3 apoptotic cascade is regulated by calcineurin-mediated BAD dephosphorylation. Calcineurin inhibitors were also proven to be effective by preventing the loss of mitochondrial membrane potential (Delta Psim) induced by Abeta, not allowing cytochrome c release from mitochondria and subsequently caspase-3 activation. Considering the results presented, we argue that calcineurin activation and BAD dephosphorylation are upstream in premitochondrial signaling events leading to caspase-3 activation in Abeta-peptide-treated cells.
Cardoso
Sandra M
SM
Center for Neuroscience and Cell Biology of Coimbra, Institute of Biochemistry, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal.
Oliveira
Catarina R
CR
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology; D004347:Drug Interactions; D004579:Electron Transport / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation; D016559:Tacrolimus / Q000494:pharmacology; D018243:Teratocarcinoma; D051025:bcl-Associated Death Protein
D016229:Amyloid beta-Peptides; C494819:BAD protein, human; D065095:Calcineurin Inhibitors; D002352:Carrier Proteins; D007166:Immunosuppressive Agents; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C074636:amyloid beta-protein (25-35); C113041:amyloid beta-protein (35-25); C090308:amyloid beta-protein (40-1); D051025:bcl-Associated Death Protein; D016572:Cyclosporine; D019703:Calcineurin; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D016559:Tacrolimus