Caspase-2 Mediates Neuronal Cell Death Induced by β-Amyloid

Abstract

β-amyloid (Aβ) has been proposed to play a role in the pathogenesis of Alzheimer's disease (AD). Deposits of insoluble Aβ are found in the brains of patients with AD and are one of the pathological hallmarks of the disease. It has been proposed that Aβ induces death by oxidative stress, possibly through the generation of peroxynitrite from superoxide and nitric oxide. In our current study, treatment with nitric oxide generators protected against Aβ-induced death, whereas inhibition of nitric oxide synthase afforded no protection, suggesting that formation of peroxynitrite is not critical for Aβ-mediated death. Previous studies have shown that aggregated Aβ can induce caspase-dependent apoptosis in cultured neurons. In all of the neuronal populations studied here (hippocampal neurons, sympathetic neurons, and PC12 cells), cell death was blocked by the broad spectrum caspase inhibitor N-benzyloxycarbonyl-val-ala-asp-fluoromethyl ketone and more specifically by the downregulation of caspase-2 with antisense oligonucleotides. In contrast, downregulation of caspase-1 or caspase-3 did not block Aβ 1–42-induced death. Neurons from caspase-2 null mice were totally resistant to Aβ 1–42 toxicity, confirming the importance of this caspase in Aβ-induced death. The results indicate that caspase-2 is necessary for Aβ 1–42-induced apoptosis in vitro.