Divergence of the apoptotic pathways induced by 4-hydroxynonenal and amyloid beta-protein

In this paper, we examine the hypothesis that 4-hydroxynonenal (HNE), a product of lipid peroxidation, is a key mediator of cell death resulting from beta-amyloid exposure. We revisit the effects of HNE on different neuronal cell types to determine which caspase or caspases are required for HNE-induced death, and to compare these results with the known caspase requirements in other death paradigms. We have previously shown that in a given neuronal cell type different death stimuli can evoke stimulus-specific apoptotic pathways. We now show that HNE treatment of neuronal cells induced dose-dependent death and caspase activity which were blocked by inhibition of caspases. Antisense down-regulation of caspases-3, -7 or -9 provided complete protection from HNE-induced death, as did down-regulation of the caspase regulators APAF-1 and DIABLO. Conversely, this work and our previous studies of three other death paradigms show that caspase-3 is not required for death induced by beta-amyloid, SOD1 down-regulation, or trophic factor deprivation. We also show that HNE accumulated in settings where death does not ensue. We conclude that HNE toxicity is mediated via a caspase-9-dependent pathway but that HNE accumulation need not induce cell death nor is it an obligate mediator of Abeta-induced cell death.