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Caspase-2 mediates neuronal cell death induced by beta-amyloid.
C M Troy1, S A Rabacchi, W J Friedman
1Department of Pathology, Taub Institute for the Study of Alzheimer's Disease, New York 10032, USA. cmt2@columbia.edu
Summary
Beta-amyloid (Abeta) triggers Alzheimer's disease cell death. Caspase-2, not oxidative stress, is essential for Abeta-induced apoptosis in neurons, as shown by blocking cell death with caspase-2 inhibitors.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Alzheimer's disease (AD) is characterized by beta-amyloid (Abeta) deposits in the brain.
- Abeta is implicated in AD pathogenesis, potentially through oxidative stress mechanisms.
- Previous research suggests aggregated Abeta induces caspase-dependent apoptosis in neurons.
Purpose of the Study:
- To investigate the role of nitric oxide and peroxynitrite in Abeta-induced neuronal death.
- To determine the specific caspases involved in Abeta-mediated apoptosis.
- To elucidate the mechanism of Abeta toxicity in neuronal cells.
Main Methods:
- Treatment with nitric oxide generators and nitric oxide synthase inhibitors.
- Utilizing a broad-spectrum caspase inhibitor (N-benzyloxycarbonyl-val-ala-asp-fluoromethyl ketone).
- Downregulation of specific caspases (caspase-2, -1, -3) using antisense oligonucleotides and employing caspase-2 null mice.
Main Results:
- Nitric oxide generators protected against Abeta-induced death, but peroxynitrite formation was not critical.
- Cell death induced by Abeta(1-42) was blocked by a broad-spectrum caspase inhibitor and specifically by caspase-2 downregulation.
- Neurons from caspase-2 null mice were resistant to Abeta(1-42) toxicity, confirming caspase-2's essential role.
Conclusions:
- The formation of peroxynitrite is not critical for Abeta-mediated neuronal death.
- Caspase-2 is a necessary mediator of Abeta(1-42)-induced apoptosis in cultured neurons.
- Targeting caspase-2 may offer a therapeutic strategy for Alzheimer's disease.