CoChat
Sign Up
Cited by 221Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchMitochondrial Function and Pathology

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

Open access
Dumont, Magali, Wille, Elizabeth, Stack, Cliona, Calingasan, Noel Y., Beal, M. Flint, Lin, Michael T.·2009·The FASEB Journal
DOI 10.1096/fj.09-132928PMC PMC2717785
Open this paper in CoChat — free account

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 Aβ pools or Aβ oligomers in Tg19959‐MnSOD mice compared to Tg19959 littermates. These data demonstrate that facilitation of the mitochondrial antioxidant response improves resistance to Aβ, slows plaque formation or increases plaque degradation, and markedly attenuates the phenotype in a transgenic AD mouse model.— Dumont, M.,Wille, E., Stack, C., Calingasan, N. Y., Beal, M. F., Lin, M. T. Reduction of oxidative stress, amyloid deposition, and memory deficit by manganese superoxide dismutase overexpression in a transgenic mouse model of Alzheimer's disease. FASEB J. 23, 2459–2466 (2009)

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1096/fj.09-132928

Cites

4 of 4 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Evidence supports a causative role for nitro-oxidative modifications in mediating early synaptic degeneration and cognitive decline in AD.

    “Evidence supports a causative role for these modifications in mediating the early synaptic degeneration and cognitive decline in AD”

    From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as Dumont et al., 2009

    The Discussion reports that MnSOD overexpression in a transgenic AD mouse model decreased brain protein oxidation, restored synaptophysin levels, and improved memory performance. This supports a role for oxidative stress in the mouse model, but the paper does not establish that specific nitro-oxidative modifications cause early synaptic degeneration or cognitive decline in people with AD. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 40

  1. Moreira P I, Nunomura A, Nakamura M, Takeda A, Shenk J C, Aliev G, Smith M A, Perry G. Nucleic acid oxidation in Alzheimer disease. Free Radic Biol Med. 2008;44:1493–1505. doi: 10.1016/j.freeradbiomed.2008.01.002. [DOI] [PubMed] [Google Scholar] · DOI
  2. Nunomura A, Moreira P I, Takeda A, Smith M A, Perry G. Oxidative RNA damage and neurodegeneration. Curr Med Chem. 2007;14:2968–2975. doi: 10.2174/092986707782794078. [DOI] [PubMed] [Google Scholar] · DOI
  3. Keller J N, Schmitt F A, Scheff S W, Ding Q, Chen Q, Butterfield D A, Markesbery W R. Evidence of increased oxidative damage in subjects with mild cognitive impairment. Neurology. 2005;64:1152–1156. doi: 10.1212/01.WNL.0000156156.13641.BA. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  4. Ringman J M, Younkin S G, Pratico D, Seltzer W, Cole G M, Geschwind D H, Rodriguez-Agudelo Y, Schaffer B, Fein J, Sokolow S, Rosario E R, Gylys K H, Varpetian A, Medina L D, Cummings J L. Biochemical markers in persons with preclinical familial Alzheimer disease. Neurology. 2008;71:85–92. doi: 10.1212/01.wnl.0000303973.71803.81. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  5. Li F, Calingasan N Y, Yu F, Mauck W M, Toidze M, Almeida C G, Takahashi R H, Carlson G A, Flint Beal M, Lin M T, Gouras G K. Increased plaque burden in brains of APP mutant MnSOD heterozygous knockout mice. J Neurochem. 2004;89:1308–1312. doi: 10.1111/j.1471-4159.2004.02455.x. [DOI] [PubMed] [Google Scholar] · DOI
  6. Melov S, Adlard P A, Morten K, Johnson F, Golden T R, Hinerfeld D, Schilling B, Mavros C, Masters C L, Volitakis I, Li Q X, Laughton K, Hubbard A, Cherny R A, Gibson B, Bush A I. Mitochondrial oxidative stress causes hyperphosphorylation of tau. PLoS ONE. 2007;2:e536. doi: 10.1371/journal.pone.0000536. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  7. Chishti M A, Yang D S, Janus C, Phinney A L, Horne P, Pearson J, Strome R, Zuker N, Loukides J, French J, Turner S, Lozza G, Grilli M, Kunicki S, Morissette C, Paquette J, Gervais F, Bergeron C, Fraser P E, Carlson G A, George-Hyslop P S, Westaway D. Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695. J Biol Chem. 2001;276:21562–21570. doi: 10.1074/jbc.M100710200. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  8. Dudal S, Krzywkowski P, Paquette J, Morissette C, Lacombe D, Tremblay P, Gervais F. Inflammation occurs early during the Abeta deposition process in TgCRND8 mice. Neurobiol Aging. 2004;25:861–871. doi: 10.1016/j.neurobiolaging.2003.08.008. [DOI] [PubMed] [Google Scholar] · DOI
  9. Hyde L A, Kazdoba T M, Grilli M, Lozza G, Brusa R, Zhang Q, Wong G T, McCool M F, Zhang L, Parker E M, Higgins G A. Age-progressing cognitive impairments and neuropathology in transgenic CRND8 mice. Behav Brain Res. 2005;160:344–355. doi: 10.1016/j.bbr.2004.12.017. [DOI] [PubMed] [Google Scholar] · DOI
  10. Lovasic L, Bauschke H, Janus C. Working memory impairment in a transgenic amyloid precursor protein TgCRND8 mouse model of Alzheimer’s disease. Genes Brain Behav. 2005;4:197–208. doi: 10.1111/j.1601-183X.2004.00104.x. [DOI] [PubMed] [Google Scholar] · DOI
  11. Bellucci A, Luccarini I, Scali C, Prosperi C, Giovannini M G, Pepeu G, Casamenti F. Cholinergic dysfunction, neuronal damage and axonal loss in TgCRND8 mice. Neurobiol Dis. 2006;23:260–272. doi: 10.1016/j.nbd.2006.03.012. [DOI] [PubMed] [Google Scholar] · DOI
  12. Raineri I, Carlson E J, Gacayan R, Carra S, Oberley T D, Huang T T, Epstein C J. Strain-dependent high-level expression of a transgene for manganese superoxide dismutase is associated with growth retardation and decreased fertility. Free Radic Biol Med. 2001;31:1018–1030. doi: 10.1016/s0891-5849(01)00686-4. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  13. Terry R D, Masliah E, Salmon D P, Butters N, DeTeresa R, Hill R, Hansen L A, Katzman R. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991;30:572–580. doi: 10.1002/ana.410300410. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  14. Pappolla M A, Chyan Y J, Omar R A, Hsiao K, Perry G, Smith M A, Bozner P. Evidence of oxidative stress and in vivo neurotoxicity of beta-amyloid in a transgenic mouse model of Alzheimer’s disease: a chronic oxidative paradigm for testing antioxidant therapies in vivo. Am J Pathol. 1998;152:871–877. [PMC free article] [PubMed] [Google Scholar]
  15. Smith M A, Hirai K, Hsiao K, Pappolla M A, Harris P L, Siedlak S L, Tabaton M, Perry G. Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress. J Neurochem. 1998;70:2212–2215. doi: 10.1046/j.1471-4159.1998.70052212.x. [DOI] [PubMed] [Google Scholar] · DOI
  16. Hartman R E, Shah A, Fagan A M, Schwetye K E, Parsadanian M, Schulman R N, Finn M B, Holtzman D M. Pomegranate juice decreases amyloid load and improves behavior in a mouse model of Alzheimer’s disease. Neurobiol Dis. 2006;24:506–515. doi: 10.1016/j.nbd.2006.08.006. [DOI] [PubMed] [Google Scholar] · DOI
  17. Daumas S, Sandin J, Chen K S, Kobayashi D, Tulloch J, Martin S J, Games D, Morris R G. Faster forgetting contributes to impaired spatial memory in the PDAPP mouse: deficit in memory retrieval associated with increased sensitivity to interference? Learn Mem. 2008;15:625–632. doi: 10.1101/lm.990208. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  18. Dumont M, Wille E, Calingasan N Y, Tampellini D, Williams C, Gouras G K, Liby K, Sporn M, Flint Beal M, Lin M T. Triterpenoid CDDO-methylamide improves memory and decreases amyloid plaques in a transgenic mouse model of Alzheimer’s disease. J Neurochem. 2009;109:502–512. doi: 10.1111/j.1471-4159.2009.05970.x. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  19. Tamagno E, Parola M, Bardini P, Piccini A, Borghi R, Guglielmotto M, Santoro G, Davit A, Danni O, Smith M A, Perry G, Tabaton M. Beta-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathways. J Neurochem. 2005;92:628–636. doi: 10.1111/j.1471-4159.2004.02895.x. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  20. Tamagno E, Bardini P, Obbili A, Vitali A, Borghi R, Zaccheo D, Pronzato M A, Danni O, Smith M A, Perry G, Tabaton M. Oxidative stress increases expression and activity of BACE in NT2 neurons. Neurobiol Dis. 2002;10:279–288. doi: 10.1006/nbdi.2002.0515. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  21. Yoshiike Y, Minai R, Matsuo Y, Chen Y R, Kimura T, Takashima A. Amyloid oligomer conformation in a group of natively folded proteins. PLoS ONE. 2008;3:e3235. doi: 10.1371/journal.pone.0003235. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  22. Huang X, Atwood C S, Hartshorn M A, Multhaup G, Goldstein L E, Scarpa R C, Cuajungco M P, Gray D N, Lim J, Moir R D, Tanzi R E, Bush A I. The A beta peptide of Alzheimer’s disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry. 1999;38:7609–7616. doi: 10.1021/bi990438f. [DOI] [PubMed] [Google Scholar] · DOI
  23. Varadarajan S, Yatin S, Kanski J, Jahanshahi F, Butterfield D A. Methionine residue 35 is important in amyloid beta-peptide-associated free radical oxidative stress. Brain Res Bull. 1999;50:133–141. doi: 10.1016/s0361-9230(99)00093-3. [DOI] [PubMed] [Google Scholar] · DOI
  24. Tabner B J, El-Agnaf O M, Turnbull S, German M J, Paleologou K E, Hayashi Y, Cooper L J, Fullwood N J, Allsop D. Hydrogen peroxide is generated during the very early stages of aggregation of the amyloid peptides implicated in Alzheimer disease and familial British dementia. J Biol Chem. 2005;280:35789–35792. doi: 10.1074/jbc.C500238200. [DOI] [PubMed] [Google Scholar] · DOI
  25. De Felice F G, Velasco P T, Lambert M P, Viola K, Fernandez S J, Ferreira S T, Klein W L. Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J Biol Chem. 2007;282:11590–11601. doi: 10.1074/jbc.M607483200. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  26. Behl C, Davis J, Cole G M, Schubert D. Vitamin E protects nerve cells from amyloid beta protein toxicity. Biochem Biophys Res Commun. 1992;186:944–950. doi: 10.1016/0006-291x(92)90837-b. [DOI] [PubMed] [Google Scholar] · DOI
  27. Yatin S M, Aksenov M, Butterfield D A. The antioxidant vitamin E modulates amyloid beta-peptide-induced creatine kinase activity inhibition and increased protein oxidation: implications for the free radical hypothesis of Alzheimer’s disease. Neurochem Res. 1999;24:427–435. doi: 10.1023/a:1020997903147. [DOI] [PubMed] [Google Scholar] · DOI
  28. Sung S, Yao Y, Uryu K, Yang H, Lee V M, Trojanowski J Q, Pratico D. Early vitamin E supplementation in young but not aged mice reduces Abeta levels and amyloid deposition in a transgenic model of Alzheimer’s disease. FASEB J. 2004;18:323–325. doi: 10.1096/fj.03-0961fje. [DOI] [PubMed] [Google Scholar] · DOI
  29. Keller J N, Kindy M S, Holtsberg F W, St Clair D K, Yen H C, Germeyer A, Steiner S M, Bruce-Keller A J, Hutchins J B, Mattson M P. Mitochondrial manganese superoxide dismutase prevents neural apoptosis and reduces ischemic brain injury: suppression of peroxynitrite production, lipid peroxidation, and mitochondrial dysfunction. J Neurosci. 1998;18:687–697. doi: 10.1523/JNEUROSCI.18-02-00687.1998. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  30. Murray I V, Liu L, Komatsu H, Uryu K, Xiao G, Lawson J A, Axelsen P H. Membrane-mediated amyloidogenesis and the promotion of oxidative lipid damage by amyloid beta proteins. J Biol Chem. 2007;282:9335–9345. doi: 10.1074/jbc.M608589200. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  31. Liu L, Komatsu H, Murray I V, Axelsen P H. Promotion of amyloid beta protein misfolding and fibrillogenesis by a lipid oxidation product. J Mol Biol. 2008;377:1236–1250. doi: 10.1016/j.jmb.2008.01.057. [DOI] [PubMed] [Google Scholar] · DOI
  32. Bieschke J, Zhang Q, Powers E T, Lerner R A, Kelly J W. Oxidative metabolites accelerate Alzheimer’s amyloidogenesis by a two-step mechanism, eliminating the requirement for nucleation. Biochemistry. 2005;44:4977–4983. doi: 10.1021/bi0501030. [DOI] [PubMed] [Google Scholar] · DOI
  33. Jucker M, Heppner F L. Cerebral and peripheral amyloid phagocytes: an old liaison with a new twist. Neuron. 2008;59:8–10. doi: 10.1016/j.neuron.2008.06.014. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  34. Town T, Laouar Y, Pittenger C, Mori T, Szekely C A, Tan J, Duman R S, Flavell R A. Blocking TGF-beta-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nat Med. 2008;14:681–687. doi: 10.1038/nm1781. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  35. Selkoe D J. Alzheimer’s disease is a synaptic failure. Science. 2002;298:789–791. doi: 10.1126/science.1074069. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  36. Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R. APP processing and synaptic function. Neuron. 2003;37:925–937. doi: 10.1016/s0896-6273(03)00124-7. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  37. Cirrito J R, Yamada K A, Finn M B, Sloviter R S, Bales K R, May P C, Schoepp D D, Paul S M, Mennerick S, Holtzman D M. Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron. 2005;48:913–922. doi: 10.1016/j.neuron.2005.10.028. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  38. Papadia S, Soriano F X, Leveille F, Martel M A, Dakin K A, Hansen H H, Kaindl A, Sifringer M, Fowler J, Stefovska V, McKenzie G, Craigon M, Corriveau R, Ghazal P, Horsburgh K, Yankner B A, Wyllie D J, Ikonomidou C, Hardingham G E. Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses. Nat Neurosci. 2008;11:476–487. doi: 10.1038/nn2071. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  39. Siedlak S L, Casadesus G, Webber K M, Pappolla M A, Atwood C S, Smith M A, Perry G. Chronic antioxidant therapy reduces oxidative stress in a mouse model of Alzheimer’s disease. Free Radic Res. 2009;43:156–164. doi: 10.1080/10715760802644694. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  40. Joseph J A, Denisova N A, Arendash G, Gordon M, Diamond D, Shukitt-Hale B, Morgan D. Blueberry supplementation enhances signaling and prevents behavioral deficits in an Alzheimer disease model. Nutr Neurosci. 2003;6:153–162. doi: 10.1080/1028415031000111282. [DOI] [PubMed] [Google Scholar] · DOI

Cited by

Sorted by citations

Authors
Dumont, M., Wille, E., Stack, C., Calingasan, N. Y., Beal, M. F., & Lin, M. T.
Affiliations
Weill Cornell Medicine (US)
Corresponding author
Lin, Michael T.
ORCID
Venue
The FASEB Journal
Publisher
Wiley
Published
2009-04-03
Volume
23
Issue
8
Pages
2459-2466
ISSN
  • 0892-6638 (ISSN-L)
  • 1530-6860
DOI
10.1096/fj.09-132928
PMC
PMC2717785
OpenAlex
W2033710792
Cited by
221
References
4
Citations by year
2026: 5 · 2025: 5 · 2024: 3 · 2023: 8 · 2022: 6 · 2021: 9 · 2020: 16 · 2019: 11 · 2018: 9 · 2017: 12 · 2016: 17 · 2015: 14 · 2014: 16 · 2013: 19 · 2012: 11
FWCI
15.50
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • The FASEB Journal (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institutes of Health (AG20729)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
Alzheimer's disease, manganese superoxide dismutase, oxidative stress, amyloid deposition, amyloid plaques, memory impairment, transgenic mouse model, catalase, oxidized proteins, synaptophysin, amyloid-beta
MeSH terms
Alzheimer Disease, Animals, Brain, Catalase, Disease Models, Animal, Female, Humans, Male, Memory Disorders, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Recombinant Proteins, Superoxide Dismutase, Gene Expression, Amyloid beta-Protein Precursor, Synaptophysin, Oxidative Stress, Mice, Plaque, Amyloid

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review