Early Induction of Oxidative Stress in Mouse Model of Alzheimer Disease with Reduced Mitochondrial Superoxide Dismutase Activity

Abstract

While oxidative stress has been linked to Alzheimer's disease, the underlying pathophysiological relationship is unclear. To examine this relationship, we induced oxidative stress through the genetic ablation of one copy of mitochondrial antioxidant superoxide dismutase 2 (Sod2) allele in mutant human amyloid precursor protein (hAPP) transgenic mice. The brains of young (5–7 months of age) and old (25–30 months of age) mice with the four genotypes, wild-type (Sod2+/+), hemizygous Sod2 (Sod2+/−), hAPP/wild-type (Sod2+/+), and hAPP/hemizygous (Sod2+/−) were examined to assess levels of oxidative stress markers 4-hydroxy-2-nonenal and heme oxygenase-1. Sod2 reduction in young hAPP mice resulted in significantly increased oxidative stress in the pyramidal neurons of the hippocampus. Interestingly, while differences resulting from hAPP expression or Sod2 reduction were not apparent in the neurons in old mice, oxidative stress was increased in astrocytes in old, but not young hAPP mice with either Sod2+/+ or Sod2+/−. Our study shows the specific changes in oxidative stress and the causal relationship with the pathological progression of these mice. These results suggest that the early neuronal susceptibility to oxidative stress in the hAPP/Sod2+/− mice may contribute to the pathological and behavioral changes seen in this animal model.

Cerebral Oxidative Stress and Microvasculature Defects in TNF-α Expressing Transgenic and Porphyromonas gingivalis-Infected ApoE–/– Mice

“…This data suggests that even wild-type mice experience intrinsic exposure to basal levels of ROS, due to by-products of normal physiological and metabolic processes. This led to the notion that the gradual accumulation of oxidative stress-related proteins was possible in these mice, as antioxidative and repair mechanisms are not being completely (100%) efficient [45][46][47][48][49]. Although the extent of oxidative protein damage from the frontal lobe brain region in wild- shown P. gingivalis can not only survive host's oxidative burst, but also has the ability to subvert its own oxidative stress via rubreythrin gene activation [12].…”

Antioxidant gene therapy against neuronal cell death

“…Genetic ablation of one copy of the MnSOD allele SOD2(+/−) in mutant human APP (hAPP) transgenic mice exacerbates the Aβ burden and significantly increases the levels of phosphorylated tau and oxidative stress (Esposito et al, 2006; Lee et al, 2012a; Li et al, 2004; Melov et al, 2007). Conversely, the overexpression of MnSOD in hAPP mice reduces oxidative stress and amyloid deposition (Dumont et al, 2009).…”

“…Interestingly, while mice deficient in X c − system have no alterations in brain GSH content, EAAT3-deficient mice have reduced GSH levels (Aoyama et al, 2006; Aoyama et al, 2008). EAAT3 knockout mice are more susceptible to ischemia-induced oxidative stress (Li et al, 2011a). …”

The role of DNA repair in brain related disease pathology

“…Overall, prevailing studies show that elevated DNA oxidative damage and dysfunctional repair might be involved in the pathology of AD and PD (65). Further studies are necessary to investigate and understand the differential expression and activities of DNA glycosylases in both diseases.…”