Mitochondrial superoxide contributes to blood flow and axonal transport deficits in the Tg2576 mouse model of Alzheimer's disease - PubMed (original) (raw)

Mitochondrial superoxide contributes to blood flow and axonal transport deficits in the Tg2576 mouse model of Alzheimer's disease

Cynthia A Massaad et al. PLoS One. 2010.

Abstract

Background: Alzheimer's disease (AD) is a neurodegenerative disease characterized by the progressive decline in cognitive functions and the deposition of aggregated amyloid beta (Abeta) into senile plaques and the protein tau into tangles. In addition, a general state of oxidation has long been known to be a major hallmark of the disease. What is not known however, are the mechanisms by which oxidative stress contributes to the pathology of AD.

Methodology/principal findings: In the current study, we used a mouse model of AD and genetically boosted its ability to quench free radicals of specific mitochondrial origin. We found that such manipulation conferred to the AD mice protection against vascular as well as neuronal deficits that typically affect them. We also found that the vascular deficits are improved via antioxidant modulation of the endothelial nitric oxide synthase, an enzyme primarily responsible for the production of nitric oxide, while neuronal deficits are improved via modulation of the phosphorylation status of the protein tau, which is a neuronal cytoskeletal stabilizer.

Conclusions/significance: These findings directly link free radicals of specific mitochondrial origin to AD-associated vascular and neuronal pathology.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1

Figure 1. SOD-2 overexpression improves the regional cerebral blood flow (rCBF) deficits displayed in Tg2576 mice.

A) The graph represents the regional cerebral blood flow (rCBF) levels in 12 to 16 months old WT, SOD-2, Tg2576 and Tg2576/SOD-2 mice as measured by MRI (ASL). Significance was assessed by a one-way ANOVA with Dunnett's post-test for multiple comparisons. ** p<0.01.

Figure 2

Figure 2. SOD-2 overexpression prevents increases in phospho-eNOS-ser1177 in Tg2576 mice.

A) Graph represents quantification of the levels of phospho-eNOS-ser1177 normalized to total eNOS from 12 to 16 months old cortical homogenates of WT, SOD-2, Tg2576 and Tg2576/SOD-2 mice. Significance was assessed by one way ANOVA with Dunnett's post-test for multiple comparisons. *p<0.05. B) Representative Western blot of phospho-eNOS-Ser1177, total eNOS and β-actin from cortical homogenates of 12 to 16 months old WT, SOD-2, Tg2576 and Tg2576/SOD-2 mice.

Figure 3

Figure 3. SOD-2 overexpression improves the axonal transport deficits displayed by Tg2576 mice.

A) The graph represents the rates on axonal transport as measured in vivo by MEMRI in 12 to 16 months old WT, SOD-2, Tg2576 and Tg2576/SOD-2 mice. Significance was assessed by a one-way ANOVA with Dunnett's post-test for multiple comparisons. ** p<0.01. B) Representative MR images with a pseudo-color overlay showing manganese accumulation in the region of interest (indicated by an arrow) in the olfactory bulb of 12 to 16 months old WT, SOD-2, Tg2576 and Tg2576/SOD-2 mice. Top row images represent the first repetition of the scan, where axonal transport of manganese has not started yet. Bottom row images represent the last repetition of the scan, where most of the manganese has already accumulated in the region of interest. Note that for the Tg2576 mice, no manganese accumulated in the region of interest which is indicative of deficient axonal transport. In the Tg2576/SOD-2 mice, accumulation of manganese is intact, indicating recovered axonal transport. The two images from each animal are on the same brightness scale.

Figure 4

Figure 4. SOD-2 overexpression prevents increases in phospho-tau-ser262 in Tg2576 mice.

A) Graph represents quantification of the levels of phospho-tau-ser262 normalized to total tau from 12 to 16 months old olfactory bulb homogenates of WT, SOD-2, Tg2576 and Tg2576/SOD-2 mice. Significance was assessed by one way ANOVA with Dunnett's post-test for multiple comparisons. *p<0.05; **p<0.01. B) Representative Western blot of phospho-tau-Ser262, total tau and β-actin from olfactory bulb homogenates of 12 to 16 months old WT, SOD-2, Tg2576 and Tg2576/SOD-2 mice.

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