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-APP695SDL mice, which have low levels of Aβ and no plaque load. In contrast, Thy1-APP751SL mice show high Aβ 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, β-amyloidogenic cleavage of APP was increased in female Thy1-APP751SL mice, which also showed increased HNE levels with simultaneously reduced Cu/Zn-SOD activity earlier than male Thy1-APP751SL mice. Our results demonstrate that impaired Cu/Zn-SOD activity contributes to oxidative damage in Thy1-APP751SL transgenic mice, and these findings are closely linked to increased β-amyloidogenic cleavage of APP.

Keywords

• Aging
• Alzheimer's disease
• Amyloid beta
• Amyloid precursor protein APP
• Gender
• Lipid peroxidation