title: Impaired Cu/Zn-SOD activity contributes to increased oxidative damage in APP transgenic mice.
abstract: Oxidative stress plays an important role in the pathogenesis of Alzheimer's disease. To determine which mechanisms cause the origin of oxidative damage, we analyzed enzymatic antioxidant defense (Cu/Zn-superoxide dismutase Cu/Zn-SOD, glutathione peroxidase GPx and glutathione reductase GR) and lipid peroxidation products malondialdehyde MDA and 4-hydroxynonenal HNE in two different APP transgenic mouse models at 3-4 and 12-15 months of age. No changes in any parameter were observed in brains from PDGF-APP695(SDL) mice, which have low levels of Abeta and no plaque load. In contrast, Thy1-APP751(SL) mice show high Abeta accumulation with aging and plaques from an age of 6 months. In brains of these mice, HNE levels were increased at 3 months (female transgenic mice) and at 12 months (both gender), that is, before and after plaque deposition, and the activity of Cu/Zn-SOD was reduced. Interestingly, beta-amyloidogenic cleavage of APP was increased in female Thy1-APP751(SL) mice, which also showed increased HNE levels with simultaneously reduced Cu/Zn-SOD activity earlier than male Thy1-APP751(SL) mice. Our results demonstrate that impaired Cu/Zn-SOD activity contributes to oxidative damage in Thy1-APP751(SL) transgenic mice, and these findings are closely linked to increased beta-amyloidogenic cleavage of APP.
authors.affiliation: Department of Pharmacology, Biocentre, J.W. Goethe University of Frankfurt, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Schuessel
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schäfer
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Bayer
authors.forename: Christian
authors.initials: C
authors.lastname: Czech
authors.forename: Laurent
authors.initials: L
authors.lastname: Pradier
authors.forename: Franz
authors.initials: F
authors.lastname: Müller-Spahn
authors.forename: Walter E
authors.initials: WE
authors.lastname: Müller
authors.forename: Anne
authors.initials: A
authors.lastname: Eckert
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism; D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000235:genetics; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000235:genetics*; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012727:Sex Characteristics; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D000447:Aldehydes; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008315:Malondialdehyde; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005980:Glutathione Reductase; C027576:4-hydroxy-2-nonenal