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Published on: February 15, 2020
Oxidative damage increased in presenilin1/presenilin2 conditional double knockout mice
Dong-Li Zhang1, Yi-Qun Chen, Xu Jiang
1Shanghai 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.
Neuroscience Bulletin
|May 19, 2009
Summary
Oxidative damage, particularly DNA lesions, correlated with neurodegeneration in presenilin knockout mice, even without Abeta(42) buildup. Inflammatory mediators may trigger this damage.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Presenilin proteins (PS1 and PS2) are crucial in Alzheimer's disease pathogenesis.
- Oxidative stress is implicated in neurodegenerative diseases, but its specific role in PS-deficient models is not fully understood.
Purpose of the Study:
- To characterize the oxidative damage profile in the brain of presenilin1 and presenilin2 conditional double knockout (dKO) mice.
- To investigate the correlation between oxidative stress markers and Alzheimer's-like phenotypes in dKO mice at different age stages.
Main Methods:
- Quantification of amyloid-beta 42 (Abeta(42)) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) using ELISA.
- Assessment of lipid peroxidation (malondialdehyde) and protein oxidation (carbonyl groups) via thiobarbituric acid and DNPH assays.
- Measurement of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activities using commercial assay kits.
Main Results:
- Abeta(42) levels were significantly decreased in dKO cortex at 6 months.
- Lipid peroxidation increased in dKO cortex at 3 months, while protein oxidation remained largely unchanged.
- Urinary 8-OHdG, a DNA damage marker, significantly decreased in dKO mice from 3 to 12 months.
- GSH-PX activity showed a significant increase in dKO mice at 9 months, with no other significant changes in antioxidant enzyme activities.
Conclusions:
- Oxidative damage, particularly DNA lesions, is correlated with neurodegenerative symptoms in dKO mice, independent of Abeta(42) deposition.
- Activated microglia and astrocytes releasing inflammatory mediators are potential triggers of oxidative damage in this model.
- These findings highlight the complex interplay between oxidative stress, inflammation, and neurodegeneration in the absence of significant amyloid pathology.
