Oxidative damage increased in presenilin1/presenilin2 conditional double knockout mice.
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 Abeta(42) 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 Abeta(42) 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.


CONCLUSIONS
Oxidative damage, especially DNA lesion, was correlated with the neurodegenerative symptoms that appeared in dKO mice without the deposition of Abeta(42). Triggers of oxidative damage could be the inflammatory mediators released by activated microglia and astrocytes.
Zhang
Dong-Li
DL
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.
Chen
Yi-Qun
YQ
Jiang
Xu
X
Ji
Ting-Ting
TT
Mei
Bing
B
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000652:urine; D000818:Animals; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000652:urine; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005978:Glutathione / Q000378:metabolism; D006834:Hydrazines / Q000378:metabolism; D015227:Lipid Peroxidation / Q000235:genetics; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D018345:Mice, Knockout / Q000502:physiology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D010446:Peptide Fragments / Q000652:urine; D053764:Presenilin-1 / Q000172:deficiency*; D053766:Presenilin-2 / Q000172:deficiency*; D013054:Spectrophotometry, Atomic / Q000379:methods; D013482:Superoxide Dismutase / Q000378:metabolism
D016229:Amyloid beta-Peptides; D006834:Hydrazines; D010446:Peptide Fragments; D053764:Presenilin-1; D053766:Presenilin-2; C075222:amyloid beta-protein (1-42); C446799:dinitrophenylhydrazine; D008315:Malondialdehyde; D000080242:8-Hydroxy-2'-Deoxyguanosine; D013482:Superoxide Dismutase; D003849:Deoxyguanosine; D005978:Glutathione