title: Loss of thioredoxin function in retinas of mice overexpressing amyloid β.
abstract: Amyloid β peptides (Aβ) have been implicated in the pathogenesis of age-related macular degeneration (ARMD) and glaucoma. In this study, retinas of mice overexpressing Aβ (Tg) were compared to those of wild-type mice (Wt) and analyzed for oxidative stress parameters. We observed a progressive decrease in all retinal cell layers, which was significantly greater in Tg mice at 14 months and culminated in loss of the outer retina at 18 months of age. We also observed higher levels of reactive oxygen species, glial fibrillary acidic protein, and hydroperoxide in Tg versus Wt mice (14 months). These effects were associated with phosphorylation/activation of the apoptosis signal kinase 1 and the p38 mitogen-activated kinase. Western blotting analysis revealed progressive increases in the levels of thioredoxin 1 and thioredoxin inhibitory protein in Tg compared to Wt mice. No changes were observed in the levels of thioredoxin reductase 1 (TrxR1); however, measurements of TrxR1 activity showed a 42.7±8% reduction in Tg mice versus Wt at 14 months of age. Our data suggest that Aβ-mediated retinal neurotoxicity involves impairment of the thioredoxin system and enhanced oxidative stress, potentially implicating this mechanism in the pathogenesis of ARMD and glaucoma.
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Health Sciences University, Augusta, GA 30912, USA.
authors.forename: Folami
authors.initials: F
authors.lastname: Lamoke
authors.forename: Guido
authors.initials: G
authors.lastname: Ripandelli
authors.forename: Scott
authors.initials: S
authors.lastname: Webster
authors.forename: Annalisa
authors.initials: A
authors.lastname: Montemari
authors.forename: Annamaria
authors.initials: A
authors.lastname: Maraschi
authors.forename: Pamela
authors.initials: P
authors.lastname: Martin
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Marcus
authors.forename: Gregory I
authors.initials: GI
authors.lastname: Liou
authors.forename: Manuela
authors.initials: M
authors.lastname: Bartoli
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000682:Amyloid / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D004789:Enzyme Activation; D015870:Gene Expression; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D008268:Macular Degeneration / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology; D054481:Thioredoxin Reductase 1 / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000447:Aldehydes; D000682:Amyloid; D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; D005904:Glial Fibrillary Acidic Protein; D017382:Reactive Oxygen Species; C445672:Txnip protein, mouse; D013879:Thioredoxins; D054481:Thioredoxin Reductase 1; C516125:Txnrd1 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; C505409:Casp3 protein, mouse; D053148:Caspase 3; C027576:4-hydroxy-2-nonenal