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J. Biol. Chem., Vol. 282, Issue 42, 30523-30534, October 19, 2007

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Increase in Expression Levels and Resistance to Sulfhydryl Oxidation of Peroxiredoxin Isoforms in Amyloid -Resistant Nerve Cells^*

Robert C. Cumming¹, Richard Dargusch, Wolfgang H. Fischer, and David Schubert²

From the Salk Institute for Biological Studies, Cellular Neurobiology Laboratory and Peptide Biology Laboratory, La Jolla, California 92037

Peroxiredoxins (Prxs) are a ubiquitously expressed family of thiol peroxidases that reduce hydrogen peroxide, peroxynitrite, and hydroperoxides using a highly conserved cysteine. There is substantial evidence that oxidative stress elicited by amyloid (A) accumulation is a causative factor in the pathogenesis of Alzheimer disease (AD). Here we show that A-resistant PC12 cell lines exhibit increased expression of multiple Prx isoforms with reduced cysteine oxidation. A-resistant PC12 cells also display higher levels of thioredoxin and thioredoxin reductase, two enzymes critical for maintaining Prx activity. PC12 cells and rat primary hippocampal neurons transfected with wild type Prx1 exhibit increased A resistance, whereas mutant Prx1, lacking a catalytic cysteine, confers no protection. Using an antibody that specifically recognizes sulfinylated and sulfonylated Prxs, it is demonstrated that primary rat cortical nerve cells exposed to A display a time-dependent increase in cysteine oxidation of the catalytic site of Prxs that can be blocked by the addition of the thiol-antioxidant N-acetylcysteine. In support of previous findings, expression of Prx1 is higher in post-mortem human AD cortex tissues than in age-matched controls. In addition, two-dimensional gel electrophoresis and mass spectrometry analysis revealed that Prx2 exists in a more oxidized state in AD brains than in control brains. These findings suggest that increased Prx expression and resistance to sulfhydryl oxidation in A-resistant nerve cells is a compensatory response to the oxidative stress initiated by chronic pro-oxidant A exposure.

Received for publication, January 30, 2007 , and in revised form, August 28, 2007.

^* This work was supported in part by the National Institutes of Health (to D. S.). 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.

¹ Fellowship support was provided by the Bundy Foundation, the John Douglas French Alzheimer's Foundation, and the Canadian Institutes of Health Research.

² To whom correspondence should be addressed: The Salk Institute for Biological Studies, Cellular Neurobiology Laboratory, 10010 N. Torrey Pines Rd., La Jolla CA 92037. Tel.: 858-453-4100; Fax: 858-535-9062; E-mail: schubert{at}salk.edu.

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