Impaired Cu/Zn-SOD activity contributes to increased oxidative damage in APP transgenic mice

Neurobiology of Disease

卷:18

Laurent Pradier¹  Franz Müller-Spahn²  Katrin Schuessel³  Anne Eckert³  Thomas A. Bayer⁴  Stephanie Schäfer⁴  Christian Czech⁵  Walter E. Müller⁶ 

[1] Aventis Pharma, Research and Development, F-94403 Vitry-sur-Seine, France;

[2] Department of Pharmacology, Biocentre, J.W. Goethe University of Frankfurt, Germany;

[3] Department of Psychiatry, Division of Neurobiology, University of the Saarland Medical Center, D-66421 Homburg, Germany;

[4] F. Hoffmann-La Roche AG, CNS Research, CH-4070 Basel, Switzerland;

[5] Neurobiology Research Laboratory, Psychiatry University Hospital, CH-4025 Basel, Switzerland;

关键词: Aging;    Alzheimer's disease;    Amyloid beta;    Amyloid precursor protein APP;    Gender;    Lipid peroxidation;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown