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The Journal of Neuroscience, February 15, 2000, 20(4):1386-1392
Caspase-2 Mediates Neuronal Cell Death Induced by  -Amyloid
Carol M.
Troy,
Sylvia A.
Rabacchi,
Wilma J.
Friedman,
Thierry F.
Frappier,
Kristy
Brown, and
Michael L.
Shelanski
Department of Pathology, Taub Institute for the Study of
Alzheimer's Disease and the Aging Brain and the Center for
Neurobiology and Behavior, Columbia University College of Physicians
and Surgeons, New York, New York 10032
 -amyloid (A) has been proposed to play a role in the
pathogenesis of Alzheimer's disease (AD). Deposits of insoluble A 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
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 A-induced
death, whereas inhibition of nitric oxide synthase afforded no
protection, suggesting that formation of peroxynitrite is not critical
for A-mediated death. Previous studies have shown that aggregated
A 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 A1-42-induced
death. Neurons from caspase-2 null mice were totally resistant to
A1-42 toxicity, confirming the importance of this
caspase in A-induced death. The results indicate that caspase-2 is
necessary for A1-42-induced apoptosis in
vitro.
Key words:
-amyloid; neuronal cell death; caspases; caspase-2; hippocampal neurons; PC12 cells; sympathetic neurons
Copyright © 2000 Society for Neuroscience 0270-6474/00/2041386-07$05.00/0
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