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J. Biol. Chem., Vol. 279, Issue 49, 51451-51459, December 3, 2004

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Fibrillar Amyloid- Peptides Kill Human Primary Neurons via NADPH Oxidase-mediated Activation of Neutral Sphingomyelinase

IMPLICATIONS FOR ALZHEIMER'S DISEASE^*

Arundhati Jana and Kalipada Pahan

From the Section of Neuroscience, Department of Oral Biology, University of Nebraska Medical Center, Lincoln, Nebraska 68583

Alzheimer's disease is a major illness of dementia characterized by the presence of amyloid plaques, neurofibrillary tangles, and extensive neuronal apoptosis. However, the mechanism behind neuronal apoptosis in the Alzheimer's-diseased brain is poorly understood. This study underlines the importance of neutral sphingomyelinase in fibrillar A peptide-induced apoptosis and cell death in human primary neurons. A1–42 peptides induced the activation of sphingomyelinases and the production of ceramide in neurons. Interestingly, neutral (N-SMase), but not acidic (A-SMase), sphingomyelinase was involved in A1–42-mediated neuronal apoptosis and cell death. A1–42-induced production of ceramide was redox-sensitive, as reactive oxygen species were involved in the activation of N-SMase but not A-SMase. A1–42 peptides induced the NADPH oxidase-mediated production of superoxide radicals in neurons that was involved in the activation of N-SMase, but not A-SMase, via hydrogen peroxide. Consistently, superoxide radicals generated by hypoxanthine and xanthine oxidase also induced the activation of N-SMase, but not A-SMase, through a catalase-sensitive pathway. Furthermore, antisense knockdown of p22phox, a subunit of NADPH oxidase, inhibited A1–42-induced neuronal apoptosis and cell death. These studies suggest that fibrillar A1–42 peptides induce neuronal apoptosis through the NADPH oxidase-superoxide-hydrogen peroxide-NS-Mase-ceramide pathway.

Received for publication, April 26, 2004 , and in revised form, September 14, 2004.

^* This study was supported by Grants NS39940 and AG19487 from National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Section of Neuroscience, Department of Oral Biology, University of Nebraska Medical Center, 40th and Holdrege, Lincoln, NE 68583-0740. Tel.: 402-472-1324; Fax: 402-472-2551; E-mail: kpahan{at}unmc.edu.

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