Impaired Cu/Zn-SOD activity contributes to increased oxidative damage in APP transgenic mice.
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.
Schuessel
Katrin
K
Department of Pharmacology, Biocentre, J.W. Goethe University of Frankfurt, Germany.
Schäfer
Stephanie
S
Bayer
Thomas A
TA
Czech
Christian
C
Pradier
Laurent
L
Müller-Spahn
Franz
F
Müller
Walter E
WE
Eckert
Anne
A
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
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