Oxidative DNA damage in the aging mouse brain

Abstract

The brain exhibits regional vulnerabilities to many insults, and age itself has differential effects on neuronal populations as exemplified by the age‐dependent loss of dopaminergic neurons in the nigrostriatal system. We hypothesized that oxidative damage to DNA was more likely to occur in the nigrostriatal system which undergoes significant neurochemical and functional changes with age. To test this hypothesis, oxidative damage to DNA, indicated by levels of 8‐hydroxy‐2′‐deoxyguanosine (oxo8dG), was measured in pons‐medulla (PM), midbrain (MB), caudate‐putamen (CP), hippocampus (HP), cerebellum (CB), and cerebral cortex (CX) at 3, 18, and 34 months of age in C57/bl mice. Steady‐state levels of oxo8dG increased significantly with age in MB, CP, and CB, but not in PM, HP, or CX. Manganese superoxide dismutase (MnSOD) activity decreased with age in MB, CP, and HP, but not in PM, CB, or CX. Regional activities of Cu/Zn superoxide dismutase (Cu/Zn SOD) and glutathione peroxidase (Glut Px) did not change significantly with age. Concomitant with the regional alterations in DNA damage, there was a significant age‐dependent decline in locomotor activity, motor coordination, and striatal dopamine content especially during the interval between 18 and 34 months. In conclusion, oxyradical‐associated damage to DNA did not accumulate uniformly across brain regions with age and was highest in brain regions that subserve spontaneous locomotor activity and motor coordination.

Comparison of lifelong and late life exercise on oxidative stress in the cerebellum

“…These results indicate that aging is coupled to an increase in cerebellar oxidative damage for a broad array of molecules. In confirmation of previous work, aging was associated with an increase in cerebellar markers of lipid [21] and DNA oxidation [4,8,30]. In addition, the currents study provides the first evidence that RNA oxidation increases in the cerebellum with advanced age.…”

Nucleic acid oxidation in Alzheimer disease

“…Lu et al [23] found that oxidative DNA damage accumulates preferentially in the promoter regions of several genes involved in synaptic plasticity, vesicular transport, and mitochondrial function. A differential accumulation of oxidative DNA lesions among brain regions has also been reported, suggesting that some areas of the brain are more prone to oxidative DNA modifications than others [110,111].…”

Coordination between Polymerase β and FEN1 Can Modulate CAG Repeat Expansion

“…The sequences and descriptions of the oligonucleotides used are shown in Table 1. DNA markers were identical to the CAG repeat-containing substrates, except they were damagefree; they corresponded to 100-nucleotide (CAG) 20 , 115-nucleotide (CAG) 25 , and 130-nucleotide (CAG) 30 . The markers were synthesized and PAGE-purified by Integrated DNA Technologies.…”

“…Although mismatch repair proteins have been shown to be essential for CAG repeat expansion (17,28), this repair pathway does not appear to account for the aging-dependence of the repeat expansion. Because aging is considered to involve increased oxidative stress (29,30), it is reasonable to suggest that the age-dependent neuronal CAG repeat expansion involves oxidative DNA damage (27,31). Indeed, a linkage between the repeat expansion in brain and oxidative DNA damage was established in a recent study (25).…”