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

Abstract

beta-amyloid (Abeta) has been proposed to play a role in the pathogenesis of Alzheimer's disease (AD). Deposits of insoluble Abeta are found in the brains of patients with AD and are one of the pathological hallmarks of the disease. It has been proposed that Abeta 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 Abeta-induced death, whereas inhibition of nitric oxide synthase afforded no protection, suggesting that formation of peroxynitrite is not critical for Abeta-mediated death. Previous studies have shown that aggregated Abeta 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 Abeta(1-42)-induced death. Neurons from caspase-2 null mice were totally resistant to Abeta(1-42) toxicity, confirming the importance of this caspase in Abeta-induced death. The results indicate that caspase-2 is necessary for Abeta(1-42)-induced apoptosis in vitro.

Apoptosome inactivation rescues proneural and neural cells from neurodegeneration

“…5 (e12.5) and found that mutant embryos showed a proliferation index twice as high as wt littermates in the rostral part of the neural tube [74.973.9 and 37.273.6% (forebrain), 28.374.1% and 26.173.0% (hindbrain), respectively; see Figure 1a]. We then checked mutant embryos at a later stage (e13.5-e14) for expression of proneural markers such as nestin, delta1, notch1, or a later marker of nerve cells (class III b-tubulin).…”

“…However, activation of Casp2 was undetectable in both ETNA cell clones. It should be mentioned that Abmediated death requires Casp2 in hippocampal neurons, sympathetic neurons and PC12 cells, 28 and requires Casp12 in primary cortical neurons. 29 This suggests that different pathways of death can be activated in different neuronal cell types.…”

Unconventional ligands and modulators of nicotinic receptors

“…Aggregated, but not soluble forms of A␤ are highly neurotoxic (Estus et al, 1997;Ferreira et al, 1997;Troy et al, 2000). However, it has been reported that there does not seem to be a direct, simple correlation between levels of insoluble (i.e., aggregated) A␤ and cognitive deficits observed in transgenic mice that express a mutant form of human APP.…”

Somatostatin and Alzheimer's disease

“…Recent studies suggest that plaques, tangles, and caspase activation share a common pathway. A can activate caspases (Harada and Sugimoto, 1999;Ivins et al, 1999;Nakagawa et al, 2000;Troy et al, 2000;Yamakava et al, 2000). Activated caspases can, in turn, cleave tau, the main component of neurofibrillary tangles.…”