Reduction of oxidative stress, amyloid deposition, and memory deficit by manganese superoxide dismutase overexpression in a transgenic mouse model of Alzheimer's disease.
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.
Weill Cornell Medical College, Department of Neurology and Neuroscience, 525 E. 68th St., New York, NY 10065, USA.
Magali
M
Dumont
Elizabeth
E
Wille
Cliona
C
Stack
Noel Y
NY
Calingasan
M Flint
MF
Beal
Michael T
MT
Lin
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002374:Catalase / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D018384:Oxidative Stress; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D016708:Synaptophysin / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D011994:Recombinant Proteins; D016708:Synaptophysin; D002374:Catalase; D013482:Superoxide Dismutase