Reduction of oxidative stress, amyloid deposition, and memory deficit by manganese superoxide dismutase overexpression in a transgenic mouse model of Alzheimer's disease

Abstract

In Alzheimer's disease (AD), oxidative stress is present early and contributes to disease pathogenesis. We previously reported that in Tg19959 transgenic AD mice, partial deficiency of the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) exacerbated amyloid pathology. We therefore asked whether MnSOD overexpression would prove beneficial against AD pathogenesis, by studying the offspring of Tg19959 mice crossed with MnSOD-overexpressing mice. At 4 mo of age, there was a 2- to 3-fold increase in MnSOD protein levels in Tg19959-MnSOD mice compared to Tg19959 littermates. Tg19959-MnSOD mice also had a 50% increase in catalase protein levels, a 50% decrease in levels of oxidized protein, and a 33% reduction in cortical plaque burden compared to Tg19959 littermates. Spatial memory was impaired and synaptophysin levels were decreased in Tg19959 mice compared to wild-type littermates, but memory and synaptophysin levels were restored to wild-type levels in Tg19959-MnSOD littermates. These benefits occurred without changes in sodium dodecyl sulfate-soluble or formic acid-soluble Abeta pools or Abeta oligomers in Tg19959-MnSOD mice compared to Tg19959 littermates. These data demonstrate that facilitation of the mitochondrial antioxidant response improves resistance to Abeta, slows plaque formation or increases plaque degradation, and markedly attenuates the phenotype in a transgenic AD mouse model.

Overexpression of Pyruvate Dehydrogenase Kinase 1 and Lactate Dehydrogenase A in Nerve Cells Confers Resistance to Amyloid β and Other Toxins by Decreasing Mitochondrial Respiration and Reactive Oxygen Species Production

“…The direct binding A␤ to the mitochondrial protein alcohol dehydrogenase (ABAD) promotes leakage of electrons, mitochondrial dysfunction, increased ROS production, and ultimately cell death (41). However, overexpression of the mitochondrial antioxidant enzyme manganese superoxide dismutase in tg-AD mice improved resistance to A␤ and attenuated the AD phenotype, suggesting that mitochondrial toxicity is central to A␤-induced cell death (44). Here, we show that overexpression of LDHA or PDK1 in nerve cells results in both decreased ⌬m and O 2 consumption, which is associated with reduced mitochondrial ROS production and attenuated cell death following exposure to various toxins, including A␤.…”

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

“…These results indicate that longevity is associated with increased activity of a complete ROS detoxification pathway in brain tissue. Transgenic overexpression of MnSOD alone confers neuroprotection in mice (Keller et al 1998;Dumont et al 2009), and the magnitude of the MnSOD elevation in brain tissue of longer lived species is sufficient that it could be similarly neuroprotective, particularly in concert with higher CAT activities. Thus, our data indicate that longer lived species might have enhanced neuroprotective capacity due to MnSOD and CAT activity.…”

Oxidative stress in Alzheimer’s disease

“…Modification of the antioxidative system by overexpressing Mn-SOD in Tg19959 APPmutated transgenic mice decreases protein oxidation and increases antioxidant defense in the brain, resulting in a reduced Aβ plaque burden and restoration of memory [107] .…”