Hippocampal long-term potentiation, memory, and longevity in mice that overexpress mitochondrial superoxide dismutase

Hu, Daoying; Cao, Peng; Thiels, Edda; Chu, Charleen T.; Wu, Gang; Oury, Tim D.; Klann, Eric

doi:10.1016/j.nlm.2006.10.003

Cited by 117 publications

(96 citation statements)

References 69 publications

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“…Interestingly, superoxide levels also progressively increased with age, with the Ͼ12-month-old mice exhibiting a higher level of superoxide than the 8-month-old mice. This is in agreement with previous reports in the literature showing an age-dependent increase in hippocampal superoxide that is returned to normal by SOD-2 overexpression (17). In Tg2576 mice, there is a further increase in superoxide that also was reduced with SOD-2 overexpression ( Fig.…”

Section: Resultssupporting

confidence: 93%

Overexpression of SOD-2 reduces hippocampal superoxide and prevents memory deficits in a mouse model of Alzheimer's disease

Massaad

Washington

Pautler

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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199

149

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Alzheimer's disease (AD) is a neurodegenerative disease characterized by impaired cognitive function and the deposition of extracellular amyloid plaques and intracellular tangles. Although the proximal cause of AD is not well understood, it is clear that amyloid-␤ (A␤) plays a critical role in AD pathology. Recent studies also implicate mitochondrial abnormalities in AD. We investigated this idea by crossing mice that overexpress mitochondrial superoxide dismutase (SOD-2) with the Tg2576 mouse model of AD that overexpresses the human amyloid precursor protein carrying the Swedish mutation (K670N:M671L). We found that overexpression of SOD-2 decreased hippocampal superoxide, prevented AD-related learning and memory deficits, and reduced A␤ plaques. Interestingly, SOD-2 overexpression did not affect the absolute levels of A␤1-40 and A␤1-42, but did significantly reduce the A␤1-42 to A␤1-40 ratio, thereby shifting the balance toward a less amyloidogenic A␤ composition. These findings directly link mitochondrial superoxide to AD pathology and demonstrate the beneficial effects of a mitochondrial anti-oxidant enzyme, hence offering significant therapeutic implications for AD.antioxidant ͉ dementia ͉ mitochondria ͉ oxidative stress ͉ reactive oxygen species

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Section: Resultssupporting

confidence: 93%

Overexpression of SOD-2 reduces hippocampal superoxide and prevents memory deficits in a mouse model of Alzheimer's disease

Massaad

Washington

Pautler

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

199

149

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“…Such a prediction seems to be gaining support from recent observations because over a certain amount SOD2 is toxic to the organism (Keaney et al 2004;Bayne et al, 2005;Ford et al, 2007). Furthermore, hyper production of SOD2 in mice can truly enhance the mitochondrial oxidative capacity (Silva et al, 2005) yet it failed to show any appreciable increase in mean life span although some increase in maximum life span was claimed (Hu et al, 2007). None of these studies however measured the Gompertz's rate of aging, so it is difficult to comment on how the mortality rate changes in these animals.…”

Section: Discussionmentioning

confidence: 93%

Reduced mitochondrial SOD displays mortality characteristics reminiscent of natural aging

Paul

Belton

Nag

et al. 2007

Mechanisms of Ageing and Development

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Manganese superoxide dismutase (MnSOD or SOD2) is a key mitochondrial enzymatic antioxidant. Arguably the most striking phenotype associated with complete loss of SOD2 in flies and mice is shortened life span. To further explore the role of SOD2 in protecting animals from aging and ageassociated pathology, we generated a unique collection of Drosophila mutants that progressively reduce SOD2 expression and function. Mitochondrial aconitase activity was substantially reduced in the Sod2 mutants, suggesting that SOD2 normally ensures the functional capacity of mitochondria. Flies with severe reductions in SOD2 expression exhibited accelerated senescence of olfactory behavior as well as precocious neurodegeneration and DNA strand breakage in neurons. Furthermore, life span was progressively shortened and age-dependent mortality was increased in conjunction with reduced SOD2 expression, while initial mortality and developmental viability were unaffected. Interestingly, life span and age-dependent mortality varied exponentially with SOD2 activity, indicating that there might normally be a surplus of this enzyme for protecting animals from premature death. Our data support a model in which disruption of the protective effects of SOD2 on mitochondria manifests as profound changes in behavioral and demographic aging as well as exacerbated age-related pathology in the nervous system.

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“…Whilst MnSOD overexpression can extend life span in flies (Sun et al 2002;Curtis et al 2007), deletion of a mitochondrial SOD gene actually increases life span in C. elegans (Van Raamsdonk and Hekimi 2009). MnSOD +/− mice have normal life spans (Van Remmen et al 2003), as do some MnSOD overexpressors (Jang et al 2009; but see Hu et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Antioxidant enzyme activities are not broadly correlated with longevity in 14 vertebrate endotherm species

Page

Richardson

Wiens

et al. 2010

AGE

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The free radical theory of ageing posits that accrual of oxidative damage underlies the increased cellular, tissue and organ dysfunction and failure associated with advanced age. In support of this theory, cellular resistance to oxidative stress is highly correlated with life span, suggesting that prevention or repair of oxidative damage might indeed be essential for longevity. To test the hypothesis that the prevention of oxidative damage underlies longevity, we measured the activities of the five major intracellular antioxidant enzymes in brain, heart and liver tissue of 14 mammalian and avian species with maximum life spans (MLSPs) ranging from 3 years to over 100 years. Our data set included Snell dwarf mice in which life span is increased by ∼50% compared to their normal littermates. We found that CuZn superoxide dismutase, the major cytosolic superoxide dismutase, showed no correlation with MLSP in any of the three organs. Similarly, neither glutathione peroxidase nor glutathione reductase activities correlated with MLSP. MnSOD, the sole mitochondrial superoxide dismutase in mammals and birds, was positively correlated with MLSP only for brain tissue. This same trend was observed for catalase. For all correlational data, effects of body mass and phylogenetic relatedness were removed using residual analysis and Felsenstein's phylogenetically independent contrasts. Our results are not consistent with a causal role for intracellular antioxidant enzymes in longevity, similar to recent reports from studies utilising genetic modifications of mice (Pérez et al., Biochim Biophys Acta 1790:1005-1014). However, our results indicate a specific augmentation of reactive oxygen species neutralising activities in brain associated with longevity.

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Hippocampal long-term potentiation, memory, and longevity in mice that overexpress mitochondrial superoxide dismutase

Cited by 117 publications

References 69 publications

Overexpression of SOD-2 reduces hippocampal superoxide and prevents memory deficits in a mouse model of Alzheimer's disease

Overexpression of SOD-2 reduces hippocampal superoxide and prevents memory deficits in a mouse model of Alzheimer's disease

Reduced mitochondrial SOD displays mortality characteristics reminiscent of natural aging

Antioxidant enzyme activities are not broadly correlated with longevity in 14 vertebrate endotherm species

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