Biogerontology

, Volume 7, Issue 1, pp 43–52 | Cite as

Elevated Oxidative Stress in the Brain of Senescence-accelerated Mice at 5 Months of Age

  • Óscar Álvarez-García
  • Ignacio Vega-Naredo
  • Verónica Sierra
  • Beatriz Caballero
  • Cristina Tomás-Zapico
  • Antonio Camins
  • José Joaquín García
  • Mercè Pallàs
  • Ana Coto-Montes
Research article

Abstract

The senescence-accelerated mouse (SAM) is a useful animal model to study aging or age-associated disorder. In the present study, we have used a multidisciplinary approach to the characterization of changes that occur in aging and in the modelling of brain aging. The SAMP8 mouse at 5 months of age exhibited an increase in gliosis and molecular oxidative damage. Likewise, we found that superoxide dismutase activity decreased compared with age-matched SAMR1 while there were no differences in activity of catalase and glutathione reductase. These results indicate that the decrease of superoxide dismutase may be involved in the increase of oxidative stress in brain of SAMP8 at younger stages. This suggestion is supported by an increase in the expression of alpha-synuclein together with phosphorylated tau protein, which is concurrent with the decline of that antioxidant enzyme. Alpha-synuclein aggregates are invariably associated with tau pathologies and our results demonstrate that alpha-synuclein accumulation is a potent inducer of tau pathologies not only in neurodegenerative diseases but also in normal aging. These results also imply that SAMP8 are exposed to elevated levels of oxidative stress from an early age, and that could be a very important cause of the senescence-related impairments and degeneration in the brain seen in this strain.

Keywords

aging alpha-synuclein antioxidant defence brain damage gliosis oxidative stress senescence-accelerated model mouse (SAM) tau phosphorylation 

Abbreviations

4HDA

4-hydroxyalkenal

AD

Alzheimer’s disease

AS

alpha-Synuclein

CAT

catalase

GR

glutathione reductase

LB

Lewy Bodies

LPO

lipid peroxidation

MDA

malondialdehyde

PD

protein damage

PHF

paired helicoidal filament

ROS

reactive oxygen species

SAM

senescence-accelerated mouse

SOD

superoxide dismutase

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Aikens, J, Dix, TA 1991Perhydroxyl radical (HOO.) initiated lipid peroxidation. The role of fatty acid hydroperoxidesJ Biol Chem2661509115098PubMedGoogle Scholar
  2. Aksenov, MY, Aksenova, MV, Butterfield, DA, Geddes, JW, Markesbery, WR 2001Protein oxidation in the brain in Alzheimer’s diseaseNeuroscience103373383CrossRefPubMedGoogle Scholar
  3. Ávila, J, Lim, F, Moreno, F, Belmonte, C, Cuello, AC 2002Tau function and dysfunction in neurons: its role in neurodegenerative disordersMol Neurobiol25213231PubMedGoogle Scholar
  4. Ávila, J 2004The influency of aging in one tauopathy: Alzheimer diseaseArch Immunol Ther Exp52410413Google Scholar
  5. Binder, LI, Frankfurter, A, Rebhun, LI 1985The distribution of tau in the mammalian central nervous systemJ Cell Biol10113711378CrossRefPubMedGoogle Scholar
  6. Boldyrev, AA, Yuneva, MO, Sorokina, EV, Kramarenko, GG, Fedorova, TN, Konovalova, GG, Lankin, VZ 2001Antioxidant systems in tissues of senescence accelerated miceBiochemistry6614301437Google Scholar
  7. Bradford, MM 1976A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein–dye bindingAnal Biochem72248254CrossRefPubMedGoogle Scholar
  8. Butterfield, DA, Howard, BJ, Yatin, S, Allen, KL, Carney, JM 1997Free radical oxidation of brain proteins in accelerated senescence and its modulation by N-tert-butyl-α-phenylnitroneProc Natl Acad Sci USA94674678CrossRefPubMedGoogle Scholar
  9. Carlson, GA, Borchelt, DR, Dake, A, Turner, S, Danielson, V, Coffin, JD, Eckman, C, Meiners, J, Nilsen, SP, Younkin, SG, Hsiao, KK 1997Genetic modification of the phenotypes produced by amyloid precursor protein overexpression in transgenic miceHum Mol Genet619511959CrossRefPubMedGoogle Scholar
  10. Choi, SY, Kwon, HY, Kwon, OB, Kang, JH 1999Hydrogen peroxide-mediated Cu,Zn-superoxide dismutase fragmentation: protection by carnosine, homocarnosine and anserineBiochim Biophys Acta1472651657PubMedGoogle Scholar
  11. Celsi, F, Ferri, A, Casciati, A, D’Ambrosi, N, Rotilio, G, Costa, A, Volonte, C, Carri, MT 2004Overexpression of of superoxide dismutase 1 protects against beta-amyloid peptide toxicity: effect of estrogen and copper chelatorsNeurochem Int442533CrossRefPubMedGoogle Scholar
  12. Clayton, DF, George, JM 1998The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and diseaseTrends Neurosci21249254CrossRefPubMedGoogle Scholar
  13. Coto-Montes, A, Hardeland, R 1999Antioxidative effects of melatonin in Drosophila melanogaster: antagonization of damage induced by inhibition of catalaseJ Pineal Res27154158PubMedGoogle Scholar
  14. Cutler, RG 1991Antioxidants and agingAm J Clin Nutr53373S379SPubMedGoogle Scholar
  15. Dickson, DW 1999Tau and synuclein and their role in neuropathologyBrain Pathol9657661PubMedGoogle Scholar
  16. Drewes, G 2004Marking tau for tangles and toxicityTrends Biochem Sci29548555CrossRefPubMedGoogle Scholar
  17. Flood, JF, Morley, JE, Reginna, M 1993Age-related changes in the pharmacological improvement of retention in senescence accelerated mouse (SAM)Neurobiol Aging14159166PubMedGoogle Scholar
  18. Frasier, M, Wolozin, B 2004Following the leader: fibrillization of alpha-synuclein and tauExp Neurol187235239CrossRefPubMedGoogle Scholar
  19. Frasier, M, Walzer, M, McCarthy, L, Magnuson, D, Lee, JM, Haas, C, Kahle, P, Wolozin, B 2005Tau phosphorylation increases in symptomatic mice overexpressing A30P alpha-synucleinExp Neurol192274287CrossRefPubMedGoogle Scholar
  20. Geddes, JW 2005Alpha-synuclein: a potent inducer of tau pathologyExp Neurol192244250CrossRefPubMedGoogle Scholar
  21. Gutteridge, JM 1984Lipid peroxidation initiated by superoxide-dependent hydroxyl radicals using complexed iron and hydrogen peroxideFEBS Lett172245249CrossRefPubMedGoogle Scholar
  22. Gutteridge, JM, Beard, AP, Quinlan, GJ 1983Superoxide-dependent lipid peroxidation. Problems with the use of catalase as a specific probe for Fenton-derived hydroxyl radicalsBiochem Biophys Res Commun117901907CrossRefPubMedGoogle Scholar
  23. Halliwell, B, Gutteridge, JM 1999Free Radicals in Biology and MedicineOxford University Press IncNew YorkGoogle Scholar
  24. Hasegawa, M, Fujiwara, H, Nonaka, T, Wakabayashi, K, Takahashi, H, Lee, VM, Trojanowski, JQ, Mann, D, Iwatsubo, T 2002Phosphorylated alpha-synuclein is ubiquitinated in alpha-synucleinopathy lesionsJ Biol Chem2774907149076CrossRefPubMedGoogle Scholar
  25. Hosokawa, M 2002A higher oxidative status accelerates senescence and aggravates age-dependent disorders in SAMP strains of miceMech Age & Dev12315531561Google Scholar
  26. Irizarry, MC, Kim, TW, McNamara, M, Tanzi, RE, George, JM, Clayton, DJ, Hyman, BT 1996Characterization of the precursor protein of the non-A beta component of senile plaques (NACP) in the human central nervous systemJ Neuropathol Exp Neurol55889895PubMedGoogle Scholar
  27. Irwin, I, DeLanney, LE, McNeill, T, Chan, P, Forno, LS, Murphy, GM,Jr, Monte, DA, Sandy, MS, Langston, JW 1994Aging and the nigrostriatal dopamine system: a non-human primate studyNeurodegeneration3251265PubMedGoogle Scholar
  28. Iwai, A, Masliah, E, Yoshimoto, M, Ge, N, Flanagan, L, Silva, HA, Kittel, A, Saitoh, T 1995The precursor protein of non-A beta component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous systemNeuron14467475CrossRefPubMedGoogle Scholar
  29. Jensen, P 1966Antimycin insensitive oxidation of succinate and reduced nicotinamide adenine nucleotide in electron transport particlesBiochim Biophys Acta157167174Google Scholar
  30. Kahle, PJ, Haas, C, Kretzschmar, HA, Neumann, M 2002Structure/function of alpha-synuclein in health and disease: rational development of animal models for Parkinson’s and related diseasesJ Neurochem82449457CrossRefPubMedGoogle Scholar
  31. Katoh-Semba, R, Kato, K 1994Age-related changes in levels of the beta-subunit of nerve growth factor in selected regions of the brain: comparison between senescence-accelerated (SAM-P8) and senescence-resistant (SAM-R1) miceNeurosci Res20251256CrossRefPubMedGoogle Scholar
  32. Kirkman, HN, Gaetani, GF 1984Catalase: a tetrameric enzyme with four tightly bound molecules of NADPHProc Natl Acad Sci USA8143434347PubMedGoogle Scholar
  33. Kosik, KS, Shimura, H 2005Phosphorylated tau and the neurodegenerative foldopathiesBiochim Biophys Acta1739298310PubMedGoogle Scholar
  34. Kum-Tatt, L, Tan, IK, Seet, AM 1975A new colorimetric method for the determination of NADH/NADPH-dependent glutathione reductase in erythrocytes and in plasmaClin Chim Acta58101108PubMedGoogle Scholar
  35. Lee, VM 2001Biomedicine Tauists and beta-aptists united–well almost!Science29314461447CrossRefPubMedGoogle Scholar
  36. Lee, VM, Giasson, BI, Trojanowski, JQ 2004More than just two peas in a pond: amyloidogenic properties of tau and alpha-synuclein in neurodegenerative diseasesTrends Neurosci27129134CrossRefPubMedGoogle Scholar
  37. Levine, RL, Garland, D, Oliver, CN, Amici, A, Climent, I, Lenz, A-G, Ahn, B-W, Shaltiel, S, Stadtman, ER 1990Determination of carbonyl content in oxidatively modified proteinsMethod Enzymol186464478Google Scholar
  38. Liu, F, Iqbal, K, Grundke-Iqbal, I, Gong, CX 2002Involvement of aberrant glycosylation in phosphorylation of tau by cdk5 and GSK-3betaFEBS Lett530209214CrossRefPubMedGoogle Scholar
  39. Lubinsky, S, Bewley, GC 1979Genetics of catalase in Drosophila melanogaster: rates of synthesis and degradation of the enzyme in flies aneuploid and euploid for the structural geneGenetics91723742Google Scholar
  40. Mandelkow, EM, Biernat, J, Drewes, G, Gustke, N, Trinczek, B, Mandelkow, E 1995Tau domains, phosphorylation, and interactions with microtubulesNeurobiol Aging16355362PubMedGoogle Scholar
  41. Martin, JP,Jr, Daily, M, Sugarman, E 1987Negative and positive assays of superoxide dismutase based on hematoxylin autoxidationArch Biochem Biophys255329336CrossRefPubMedGoogle Scholar
  42. Matsugo, S, Kitagawa, T, Minami, S, Esashi, Y, Oomura, Y, Tokumaru, S, Kojo, S, Matsushima, K, Sasaki, K 2000Age-dependent changes in lipid peroxide levels in peripheral organs, but not in brain, in senescence-accelerated miceNeurosci Lett278105108CrossRefPubMedGoogle Scholar
  43. Miyamoto, M, Kiyota, Y, Yamazaki, N, Nagaoka, A, Matsuo, T, Nagawa, Y, Takeda, T 1986Age-related changes in learning and memory in the senescence-accelerated mouse (SAM)Physiol Behav38399406CrossRefPubMedGoogle Scholar
  44. Noble, W, Olm, V, Takata, K, Casey, E, Mary, O, Meyerson, J, Gaynor, K, LaFrancois, J, Wang, L, Kondo, T, Davies, P, Burns, M, Veeranna, M, Nixon, R, Dickson, D, Matsuoka, Y, Ahlijanian, M, Lau, LF, Duff, K 2003Cdk5 is a key factor in tau aggregation and tangle formation in vivoNeuron38555565CrossRefPubMedGoogle Scholar
  45. Nomura, Y, Okuma, Y 1999Age-related defects in lifespan and learning ability in SAMP8 miceNeurobiol Aging20111115CrossRefPubMedGoogle Scholar
  46. Ohta, A, Hirano, T, Yagi, H, Tanaka, S, Hosokawa, M, Takeda, T 1989Behavioral characteristics of the SAM-P/8 strain in Sidman active avoidance taskBrain Res.498195198CrossRefPubMedGoogle Scholar
  47. Petersen, K, Olesen, OF, Mikkelsen, JD 1999Developmental expression of α-synuclein in rat hippocampus and cerebral cortexNeuroscience91651659CrossRefPubMedGoogle Scholar
  48. Radi, R, Beckman, JS, Bush, KM, Freeman, BA 1991Peroxynitrite-induced membrane lipid peroxidation: the cytotoxic potential of superoxide and nitric oxideArch Biochem Biophys288481487PubMedGoogle Scholar
  49. Reiter, RJ 1995Oxidative processes and antioxidative defense mechanisms in the aging brainFASEB J9526533PubMedGoogle Scholar
  50. Satoh, A, Yokozawa, T, Cho, EJ, Okamoto, T, Sei, Y 2004Antioxidative effects related to the potential anti-aging properties of the Chinese prescription Kangen-karyu and Carthami Flos in senescence-accelerated miceArch Gerontol Geriatr396982CrossRefPubMedGoogle Scholar
  51. Schuessel, K, Schäfer, S, Bayer, TA, Czech, C, Pradier, L, Müller-Spahn, F, Müller, WE, Eckert, A 2005Impaired Cu/Zn-SOD activity contributes to increased oxidative damage in APP transgenic miceNeurobiol Dis188999CrossRefPubMedGoogle Scholar
  52. Shendelman, S, Jonason, A, Martinat, C, Leete, T, Abeliovich, A 2004DJ-1 Is a redox-dependent molecular chaperone that inhibits alpha-synuclein aggregate formationPLoS Biol5e362Google Scholar
  53. Smith, MA, Casadesus, G, Joseph, JA, Perry, G 2002Amyloid-beta and tau serve antioxidant functions in the aging and Alzheimer brainFree Radic Biol Med3311941199PubMedGoogle Scholar
  54. Syme, CD, Blanch, EW, Holt, C, Jakes, R, Goedert, M, Hecht, L, Barron, LD 2002A Raman optical activity study of rheomorphism in caseins, synucleins and tau. New insight into the structure and behaviour of natively unfolded proteinsEur J Biochem269148156CrossRefPubMedGoogle Scholar
  55. Takeda, T, Hosokawa, M, Higuchi, K 1994Senescence-accelerated mice (SAM): a novel murine model of accelerated senescenceBrain Res9338342Google Scholar
  56. Tien, M, Svingen, BA, Aust, SD 1981Superoxide dependent lipid peroxidationFed Proc40179182PubMedGoogle Scholar
  57. Uchida, K, Kihara, N, Hashimoto, K, Nakayama, H, Yamaguchi, R, Tateyama, S 2003Age-related histological changes in the canine substantia nigraJ Vet Med Sci65179185PubMedGoogle Scholar
  58. Viani, P, Cervato, G, Fiorilli, A, Cestaro, B 1991Age-related differences in synaptosomal peroxidative damage and membrane propertiesJ Neurochem56253258PubMedGoogle Scholar
  59. Wang, DS 2003From Lewy body disease to Alzheimer’s disease: hypothesis and evidenceFront Biosci8s82238227Google Scholar
  60. Woods, YL, Cohen, P, Becker, W, Jakes, R, Goedert, M, Wang, X, Proud, CG 2001The kinase DYRK phosphorylates protein-synthesis initiation factor eIF2Bepsilon at Ser539 and the microtubule-associated protein tau at Thr212: potential role for DYRK as a glycogen synthase kinase 3-priming kinaseBiochem J355609615PubMedGoogle Scholar
  61. Yagi, H, Katoh, S, Akiguchi, I, Takeda, T 1988Age-related deterioration of ability of acquisition in memory and learning in senescence accelerated mouse: SAMP8 as an animal model of disturbances in recent memoryBrain Res4748693CrossRefPubMedGoogle Scholar
  62. Yasui, F, Matsugo, S, Ishibashi, M, Kajita, T, Esaci, Y, Oomura, Y, Kojo, S, Sasaki, K 2002Effects of chronic acetyl-l-carnitine treatment on brain lipid hydroperoxide level and passive avoidance learning in senescence-accelerated miceNeurosci Let.334177180CrossRefGoogle Scholar
  63. Yasui, F, Ishibashi, M, Matsugo, S, Kojo, S, Oomura, Y, Sasaki, K 2003aBrain lipid peroxidation level increases in senescence-accelerated mice at an earlier ageNeurosci Lett3506668CrossRefGoogle Scholar
  64. Yasui, F, Ishibashi, M, Matsugo, S, Kojo, S, Oomura, Y, Sasaki, K 2003bBrain lipid hydroperoxide level increases in senescence-accelerated mice at an early ageNeurosci Lett3506668CrossRefGoogle Scholar
  65. Zhu, LQ, Wang, SH, Ling, ZQ, Wang, DL, Wang, JZ 2004Effect of inhibiting melatonin biosynthesis on spatial memory retention and tau phosphorylation in ratJ Pineal Res377177CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2006

Authors and Affiliations

  • Óscar Álvarez-García
    • 1
  • Ignacio Vega-Naredo
    • 1
  • Verónica Sierra
    • 1
  • Beatriz Caballero
    • 1
  • Cristina Tomás-Zapico
    • 1
  • Antonio Camins
    • 2
  • José Joaquín García
    • 3
  • Mercè Pallàs
    • 2
  • Ana Coto-Montes
    • 1
  1. 1.Department of Morphology and Cellular Biology, Faculty of MedicineUniversity of OviedoOviedoSpain
  2. 2.Department of Pharmacology, Faculty of PharmacyUniversity of BarcelonaBarcelonaSpain
  3. 3.Department of Pharmacology and Physiology, Faculty of MedicineUniversity of ZaragozaSpain

Personalised recommendations