Caspase-2 mediates neuronal cell death induced by beta-amyloid

beta-amyloid (A beta) has been proposed to play a role in the pathogenesis of Alzheimer's disease (AD). Deposits of insoluble A beta are found in the brains of patients with AD and are one of the pathological hallmarks of the disease. It has been proposed that A beta induces death by oxidative stres s, possibly through the generation of peroxynitrite from superoxide and nit ric oxide. In our current study, treatment with nitric oxide generators pro tected against A beta-induced death, whereas inhibition of nitric oxide syn thase afforded no protection, suggesting that formation of peroxynitrite is not critical for A beta-mediated death. Previous studies have shown that a ggregated A beta can induce caspase-dependent apoptosis in cultured neurons . In all of the neuronal populations studied here (hippocampal neurons, sym pathetic neurons, and PC12 cells), cell death was blocked by the broad spec trum caspase inhibitor N-benzyloxycarbonylval-ala-asp-fluoromethyl ketone a nd more specifically by the downregulation of caspase-2 with antisense olig onucleotides. In contrast, downregulation of caspase-1 or caspase-3 did not block A beta 1-42-induced death. Neurons from caspase-2 null mice were tot ally resistant to A beta 1-42 toxicity, confirming the importance of this c aspase in A beta-induced death. The results indicate that caspase-2 is nece ssary for A beta 1-42 -induced apoptosis in vitro.