title: Increase in expression levels and resistance to sulfhydryl oxidation of peroxiredoxin isoforms in amyloid beta-resistant nerve cells.
abstract: 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 beta (Abeta) accumulation is a causative factor in the pathogenesis of Alzheimer disease (AD). Here we show that Abeta-resistant PC12 cell lines exhibit increased expression of multiple Prx isoforms with reduced cysteine oxidation. Abeta-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 Abeta 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 Abeta 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 Abeta-resistant nerve cells is a compensatory response to the oxidative stress initiated by chronic pro-oxidant Abeta exposure.
authors.affiliation: Salk Institute for Biological Studies, Cellular Neurobiology Laboratory and Peptide Biology Laboratory, La Jolla, California 92037, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Cumming
authors.forename: Richard
authors.initials: R
authors.lastname: Dargusch
authors.forename: Wolfgang H
authors.initials: WH
authors.lastname: Fischer
authors.forename: David
authors.initials: D
authors.lastname: Schubert
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000208:ethnology* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D020134:Catalytic Domain / Q000235:genetics; D002525:Cerebellar Cortex / Q000201:enzymology / Q000473:pathology; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D015870:Gene Expression; D006624:Hippocampus / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D016716:PC12 Cells; D054464:Peroxiredoxins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D013438:Sulfhydryl Compounds / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016166:Free Radical Scavengers; D007527:Isoenzymes; D013438:Sulfhydryl Compounds; C489898:Prdx1 protein, rat; C515940:PRDX1 protein, human; C086065:PRDX2 protein, human; D054464:Peroxiredoxins; D000111:Acetylcysteine