Involvement of calcineurin in the neurotoxic effects induced by amyloid-beta and prion peptides.
It is usually accepted that prion and amyloid-beta (A beta) peptides induce apoptotic cell death. However, the mechanisms that trigger neuronal death, induced by these amyloidogenic peptides, remain to be clarified. In the present study we analysed the neurotoxic effects of the synthetic prion and A beta peptides, PrP106-126 and A beta 25-35, in primary cultures of rat brain cortical cells. PrP106-126 and A beta 25-35 incubated at a concentration of 25 micro m for 24 h, did not affect cell membrane integrity, but decreased the metabolic capacity of the cells. The intracellular free Ca2+ concentration and reactive oxygen species levels increased significantly after 24 h treatment with PrP106-126 and A beta 25-35. Furthermore, these peptides (after 24 h exposure) also induced cytochrome c release from mitochondria and increased caspase-3-like activity. FK506, an inhibitor of the Ca2+/calmodulin-dependent phosphatase, calcineurin, was able to prevent cytochrome c release, caspase-3 activation and cell death induced by A beta 25-35 or PrP106-126 peptides. Taken together these data suggest that calcineurin is involved in A beta 25-35 and PrP106-126 neurotoxicity.
Agostinho
Paula
P
Center for Neurosciences and Faculty of Medicine, University of Coimbra, 3004-504 Coimbra. Portugal.
Oliveira
Catarina Resende
CR
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D018929:Cell Culture Techniques; D003574:Cytochrome c Group / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D015227:Lipid Peroxidation / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000633:toxicity*; D010446:Peptide Fragments / Q000633:toxicity*; D011328:Prions / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D065095:Calcineurin Inhibitors; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D009498:Neurotoxins; D010446:Peptide Fragments; D011328:Prions; D017382:Reactive Oxygen Species; C074636:amyloid beta-protein (25-35); C082632:prion protein (106-126); D019703:Calcineurin; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D002118:Calcium; D016559:Tacrolimus