Shanghai Institute of Brain Functional Genomics, and Key Laboratory of Brain Functional Genomics, Shanghai municipal and Ministry of Education, East China Normal University, Shanghai 200062, China

Abstract 

Objective 
This report aims to describe the oxidative damage profile in brain of presenilin1 and presenilin2 conditional double knockout mice (dKO) at both early and late age stages, and to discuss the correlation between oxidative stress and the Alzheimer-like phenotypes of dKO mice. 
Methods 
The protein level of Aβ42 in dKO cortex and free 8-OHdG level in urine were measured by ELISA. Thiobarbituric acid method and spectrophotometric DNPH assay were used to determine the lipid peroxidation and protein oxidation in cortex, respectively. SOD and GSH-PX activities were assessed by SOD Assay Kit-WST and GSH-PX assay kit, separately. 
Results 
Significant decrease of Aβ42 was verified in dKO cortex at 6 months as compared to control mice. Although lipid peroxidation (assessed by MDA) was increased only in dKO cortex at 3 months and protein oxidation (assessed by carbonyl groups) was basically unchanged in dKO cortex, ELISA analysis revealed that free 8-OHdG, which was an indicator of DNA lesion, was significantly decreased in urine of dKO mice from 3 months to 12 months. Activities of SOD and GSH-PX in dKO and control cortices showed no statistical difference except a significant increase of GSH-PX activity in dKO mice at 9 months. 
Conclusion 
Oxidative damage, especially DNA lesion, was correlated with the neurodegenerative symptoms that appeared in dKO mice without the deposition of Aβ42. Triggers of oxidative damage could be the inflammatory mediators released by activated microglia and astrocytes.

Keywords

presenilins; Alzheimer’s disease; oxidative damage; 8-OHdG

[SpringerLink]