Amino Acids

, Volume 32, Issue 4, pp 553–559 | Cite as

Hallmarks of protein oxidative damage in neurodegenerative diseases: focus on Alzheimer’s disease

  • M. C. Polidori
  • H. R. Griffiths
  • E. Mariani
  • P. Mecocci
Review Article


The pathogenesis of several neurodegenerative diseases, including Alzheimer’s disease, has been linked to a condition of oxidative and nitrosative stress, arising from the imbalance between increased reactive oxygen species (ROS) and reactive nitrogen species (RNS) production and antioxidant defences or efficiency of repair or removal systems. The effects of free radicals are expressed by the accumulation of oxidative damage to biomolecules: nucleic acids, lipids and proteins. In this review we focused our attention on the large body of evidence of oxidative damage to protein in Alzheimer’s disease brain and peripheral cells as well as in their role in signalling pathways. The progress in the understanding of the molecular alterations underlying Alzheimer’s disease will be useful in developing successful preventive and therapeutic strategies, since available drugs can only temporarily stabilize the disease, but are not able to block the neurodegenerative process.

Keywords: Alzheimer’s disease – Aging – Oxidative stress – Nitrosative stress – Protein 


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  1. Ahmed, N, Ahmed, U, Thornalley, PJ, Hager, K, Fleischer, G, Munch, G 2005Protein glycation, oxidation and nitration adduct residues and free adducts of cerebrospinal fluid in Alzheimer’s disease and link to cognitive impairmentJ Neurochem92255263PubMedCrossRefGoogle Scholar
  2. Andersen JK (2004) Oxidative stress in neurodegeneration: cause or consequence? Nature Rev S18–S25Google Scholar
  3. Bassett, CN, Montine, TJ 2003Lipoproteins and lipid peroxidation in Alzheimer’s diseaseJ Nutr Health Aging72429PubMedGoogle Scholar
  4. Beal, MF 2000Oxidative metabolismAnn N Y Acad Sci924164169PubMedCrossRefGoogle Scholar
  5. Beckman, KB, Ames, BN 1998The free radical theory of aging maturesPhysiol Rev78547581PubMedGoogle Scholar
  6. Berr, C, Balansard, B, Arnaud, J, Roussel, AM, Alperovitch, A 2000Cognitive decline is associated with systemic oxidative stress: the EVA study. Etude du Vieillissement ArterielJ Am Geriatr Soc4812851291PubMedGoogle Scholar
  7. Butterfield, DA 2004Proteomics: a new approach to investigate oxidative stress in Alzheimer’s disease brainBrain Res100017PubMedCrossRefGoogle Scholar
  8. Butterfield, DA, Castegna, A 2003Proteomics for the identification of specifically oxidized proteins in brain: technology and application to the study of neurodegenerative disordersAmino Acids25419425PubMedCrossRefGoogle Scholar
  9. Butterfield, DA, Kanski, J 2001Brain protein oxidation in age-related neurodegenerative disorders that are associated with aggregated proteinsMech Ageing Dev122945962PubMedCrossRefGoogle Scholar
  10. Cakatay, U, Telci, A, Kayali, R, Tekeli, F, Akcay, T, Sivas, A 2001Relation of oxidative protein damage and nitrotyrosine levels in the aging rat brainExp Gerontol36221229PubMedCrossRefGoogle Scholar
  11. Calabrese, V, Scapagnini, G, Giuffrida Stella, AM, Bates, TE, Clark, JB 2001Mitochondrial involvement in brain function and dysfunction: relevance to aging, neurodegenerative disorders and longevityNeurochem Res26739764PubMedCrossRefGoogle Scholar
  12. Carty, JL, Bevan, R, Waller, H, Mistry, N, Cooke, M, Lunec, J, Griffiths, HR 2000The effects of vitamin C supplementation on protein oxidation in healthy volunteersBiochem Biophys Res Commun273729735PubMedCrossRefGoogle Scholar
  13. Cecchi, C, Latorraca, S, Sorbi, S, Iantomasi, T, Favilli, F, Vincenzini, MT, Liguri, G 1999Glutathione level is altered in lymphoblasts from patients with familial Alzheimer’s diseaseNeurosci Lett275152154PubMedCrossRefGoogle Scholar
  14. Choi, J, Forster, MJ, McDonald, SR, Weintraub, ST, Carroll, CA, Gracy, RW 2004Proteomic identification of specific oxidized proteins in ApoE-knockout mice: relevance to Alzheimer’s diseaseFree Radic Biol Med3611551162PubMedCrossRefGoogle Scholar
  15. Conrad, CC, Marshall, PL, Talent, JM, Malakowsky, CA, Choi, J, Gracy, RW 2000Oxidized proteins in Alzheimer’s plasmaBiochem Biophys Res Commun275678681PubMedCrossRefGoogle Scholar
  16. Cross, JV, Templeton, DJ 2004Oxidative stress inhibits MEKK1 by site-specific glutathionylation in the ATP-binding domainBiochem J381675683PubMedCrossRefGoogle Scholar
  17. Davies, SM, Poljak, A, Duncan, MW, Smythe, GA, Murphy, MP 2001Measurements of protein carbonyls, ortho- and meta-tyrosine and oxidative phosphorylation complex activity in mitochondria from young and old ratsFree Radic Biol Med31181190PubMedCrossRefGoogle Scholar
  18. Engelhart, MJ, Geerlings, MI, Ruitenberg, A, van Swieten, JC, Hofman, A, Witteman, JC, Breteler, MM 2002Dietary intake of antioxidants and risk of Alzheimer diseaseJ Am Med Assoc28732233229CrossRefGoogle Scholar
  19. Frei, B eds. 1994Natural antioxidants in human health and disease1Academic PressSan DiegoGoogle Scholar
  20. Gabbita, SP, Aksenov, MY, Lovell, MA, Markesbery, WR 1999Decrease in peptide methionine sulphoxide reductase in AD brainJ Neurochem7316601666PubMedCrossRefGoogle Scholar
  21. Gale, CR, Martyn, CN, Cooper, C 1996Cognitive impairment and mortality in a cohort of elderly peopleBr Med312608611Google Scholar
  22. Goodwin, JS, Goodwin, JM, Garry, PJ 1983Association between nutritional status and cognitive functioning in a healthy elderly populationJ Am Med Assoc24929172921CrossRefGoogle Scholar
  23. Grant, MM, Barber, VS, Griffiths, HR 2005The presence of ascorbate induces expression of brain derived neurotrophic factor in SH-SY5Y neuroblastoma cells after peroxide insult, which is associated with increased survivalProteomics5534540PubMedCrossRefGoogle Scholar
  24. Griffiths, HR, Lunec, J, Blake, DR 1992Oxygen radical induced fluorescence in proteins; identification of the fluorescent tryptophan metabolite, N-formyl kynurenine, as a biological index of radical damageAmino Acids3183194CrossRefGoogle Scholar
  25. Grune, T, Davies, KJ 2003The proteasomal system and HNE-modified proteinsMol Aspects Med24195204PubMedCrossRefGoogle Scholar
  26. Hayn, M, Kremser, K, Singewald, N, Cairns, N, Nemethova, M, Lubec, B, Lubec, G 1996Evidence against the involvement of reactive oxygen species in the pathogenesis of neuronal death in Down’s syndrome and Alzheimer’s diseaseLife Sci59537544PubMedCrossRefGoogle Scholar
  27. Hensley, K, Hall, N, Subramaniam, R, Cole, P, Harris, M, Aksenov, M, Aksenova, M, Gabbita, SP, Wu, JF, Carney, JM 1995Brain regional correspondence between Alzheimer’s disease histopathology and biomarkers of protein oxidationJ Neurochem6521462156PubMedCrossRefGoogle Scholar
  28. Hensley, K, Maidt, ML, Yu, Z, Sang, H, Markesbery, WR, Floyd, RA 1998Electrochemical analysis of protein nitrotyrosine and dityrosine in the Alzheimer brain indicates region-specific accumulationJ Neurosci1881268132PubMedGoogle Scholar
  29. Horiguchi, T 2003Nitration of tau protein is linked to neurodegeneration in tauopathiesAm J Pathol16310211031PubMedGoogle Scholar
  30. Hou, L, Kang, I, Marchant, RE, Zagorski, MG 2002Methionine 35 oxidation reduces fibril assembly of the amyloid abeta (1–42) peptide of ADJ Biol Chem2774017340176PubMedCrossRefGoogle Scholar
  31. Irie, Y, Saeki, M, Kamisaki, Y, Martin, E, Murad, F 2003Histone H1.2 is a substrate for denitrase, an activity that reduces nitrotyrosine immunoreactivity in proteinsProc Natl Acad Sci USA10056345639PubMedCrossRefGoogle Scholar
  32. Jackson, MJ, Papa, S, Bolanos, J, Bruckdorfer, R, Carlsen, H, Elliott, RM, Flier, J, Griffiths, HR, Heales, S, Holst, B, Lorusso, M, Lund, E, Oivind Moskaug, J, Moser, U, Di Paola, M, Polidori, MC, Signorile, A, Stahl, W, Vina-Ribes, J, Astley, SB 2002Antioxidants, reactive oxygen and nitrogen species, gene induction and mitochondrial functionMol Aspects Med23209285PubMedCrossRefGoogle Scholar
  33. Keller, JN, Schmitt, FA, Scheff, SW, Ding, Q, Chen, Q, Butterfield, DA, Markesbery, WR 2005Evidence of increased oxidative damage in subjects with mild cognitive impairmentNeurology6411521156PubMedGoogle Scholar
  34. La Rue, A, Koehler, KM, Wayne, SJ, Chiulli, SJ, Haaland, KY, Garry, PJ 1997Nutritional status and cognitive functioning in a normally aging sample: a 6-y reassessmentAm J Clin Nutr652029PubMedGoogle Scholar
  35. Laurin, D, Masaki, KH, Foley, DJ, White, LR, Launer, LJ 2004Midlife dietary intake of antioxidants and risk of late-life incident dementia: the Honolulu-Asia Aging StudyAm J Epidemiol159959967PubMedCrossRefGoogle Scholar
  36. Leeuwenburgh, C, Wagner, P, Holloszy, JO, Sohal, RS, Heinecke, JW 1997Caloric restriction attenuates dityrosine cross-linking of cardiac and skeletal muscle proteins in aging miceArch Biochem Biophys3467480PubMedCrossRefGoogle Scholar
  37. Mecocci, P 2004Oxidative stress in mild cognitive impairment and Alzheimer disease: a continuumJ Alzheimers Dis6159163PubMedGoogle Scholar
  38. Mecocci, P, Fanò, G, Fulle, S, MacGarvey, U, Shinobu, L, Polidori, MC, Cherubini, A, Vecchiet, J, Senin, U, Beal, MF 1999Age-dependent increases in oxidative damage to DNA, lipids, and proteins in human skeletal muscleFree Radic Biol Med26303308PubMedCrossRefGoogle Scholar
  39. Mecocci, P, MacGarvey, U, Beal, MF 1994Oxidative damage to mitochondrial DNA is increased in Alzheimer’s diseaseAnn Neurol36747751PubMedCrossRefGoogle Scholar
  40. Mecocci, P, MacGarvey, U, Kaufman, AE, Koontz, D, Shoffner, JM, Wallace, DC, Beal, MF 1993Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brainAnn Neurol34609616PubMedCrossRefGoogle Scholar
  41. Mecocci, P, Polidori, MC, Cherubini, A, Ingegni, T, Mattioli, P, Catani, M, Rinaldi, P, Cecchetti, R, Stahl, W, Senin, U, Beal, MF 2002Lymphocyte oxidative DNA damage and plasma antioxidants in Alzheimer’s diseaseArch Neurol59794798PubMedCrossRefGoogle Scholar
  42. Mecocci, P, Polidori, MC, Ingegni, T, Cherubini, A, Chionne, F, Cecchetti, R, Senin, U 1998Oxidative damage to DNA in lymphocytes from AD patientsNeurology5110141017PubMedGoogle Scholar
  43. Morris, MC, Evans, DA, Bienias, JL, Tangney, CC, Bennett, DA, Aggarwal, N, Wilson, RS, Scherr, PA 2002Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community studyJ Am Med Assoc28732303237CrossRefGoogle Scholar
  44. Pappolla, MA, Omar, RA, Kim, KS, Robakis, NK 1992Immunohistochemical evidence of oxidative stress in Alzheimer diseaseAm J Pathol140621628PubMedGoogle Scholar
  45. Perrig, WJ, Perrig, P, Stähelin, HB 1997The relation between antioxidants and memory performance in the old and very oldJ Am Geriatr Soc45718724PubMedGoogle Scholar
  46. Pitchumoni, SS, Doraiswamy, PM 1998Current status of antioxidant therapy for Alzheimer’s diseaseJ Am Geriatr Soc4615661572PubMedGoogle Scholar
  47. Polidori, MC, Cherubini, A, Senin, U, Mecocci, P 2001Peripheral non-enzymatic antioxidant changes with human aging: a selective status reportBiogerontology299104PubMedCrossRefGoogle Scholar
  48. Polidori, MC, Mattioli, P, Aldred, S, Cecchetti, R, Stahl, W, Griffiths, H, Senin, U, Sies, H, Mecocci, P 2004Plasma antioxidant status, immunoglobulin G oxidation and lipid peroxidation in demented patients: relevance to Alzheimer’s disease and vascular dementiaDement Geriatr Cogn Disord18265270PubMedCrossRefGoogle Scholar
  49. Poon HF, Vaishnav RA, Getchell TV, Getchell ML, Butterfield DA (2005) Quantitative proteomics analysis of differential protein expression and oxidative modification of specific proteins in the brains of old mice. Neurobiol Aging (epub ahead of print)Google Scholar
  50. Reynolds, MR, Berry, RW, Binder, LI 2005Site specific nitration and oxidative dityrosine bridging of the tau protein by peroxynitrite implications for ADBiochemistry4416901700PubMedCrossRefGoogle Scholar
  51. Riviere, S, Birlouez-Aragon, I, Nourhashemi, F, Vellas, B 1998Low plasma vitamin C in Alzheimer patients despite an adequate dietInt J Geriatr Psychiatry13749754PubMedCrossRefGoogle Scholar
  52. Ross CA, Poirier MA (2004) Protein aggregation and neurodegenerative disease. Nature Med S10–S17Google Scholar
  53. Saitoh, M, Nishitoh, H, Fujii, M, Takeda, K, Tobiume, K, Sawada, Y, Kawabata, M, Miyazono, K, Ichijo, H 1998Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1EMBO J1725962606PubMedCrossRefGoogle Scholar
  54. Sano, M, Ernesto, C, Thomas, RG, Klauber, MR, Schafer, K, Grundman, M, Woodbury, P, Growdon, J, Cotman, CW, Pfeiffer, E, Schneider, LS, Thal, LJ 1997A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s Disease Cooperative StudyN Engl J Med33612161222PubMedCrossRefGoogle Scholar
  55. Schmidt, R, Hayn, M, Reinhart, B, Roob, G, Schmidt, H, Schumacher, M, Watzinger, N, Launer, LJ 1998Plasma antioxidants and cognitive performance in middle-aged and older adults: results of the Austrian Stroke Prevention StudyJ Am Geriatr Soc4614071410PubMedGoogle Scholar
  56. Shadel, GS 2005Mitochondrial DNA, aconitase “wraps” it upTrends Biochem Sci30294296PubMedCrossRefGoogle Scholar
  57. Short, R, Williams, DD, Bowden, DM 1997Circulating antioxidants as determinants of the rate of biological aging in pigtailed macaques (Macaca nemestrina)J Gerontol A Biol Sci Med Sci52B26B38PubMedGoogle Scholar
  58. Sies, H 1985Oxidative stress: introductory remarksSies, H eds. Oxidative stressAcademic PressOrlando17Google Scholar
  59. Smith, CD, Carney, JM, Starke-Reed, PE, Oliver, CN, Stadtman, ER, Floyd, RA, Markesbery, WR 1991Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer’s diseaseProc Natl Acad Sci USA881054010543PubMedCrossRefGoogle Scholar
  60. Smith, MA, Perry, G, Richey, PL, Sayre, LM, Anderson, VE, Beal, MF, Kowall, N 1996Oxidative damage in Alzheimer’sNature382120121PubMedCrossRefGoogle Scholar
  61. Smith, MA, Richey Harris, PL, Sayre, LM, Beckman, JS, Perry, G 1997Widespread peroxynitrite-mediated damage in Alzheimer’s diseaseJ Neurosci1726532657PubMedGoogle Scholar
  62. Sohal, RS, Agarwal, S, Dubey, A, Orr, WC 1993Protein oxidative damage is associated with life expectancy of housefliesProc Natl Acad Sci USA9072557259PubMedCrossRefGoogle Scholar
  63. Song, S, Jung, YK 2004Alzheimer’s disease meets the ubiquitin-proteasome systemTrends Mol Med10565570PubMedCrossRefGoogle Scholar
  64. Stadtman, ER, Moskovitz, J, Levine, RL 2003Oxidation of methionine residues of proteins: biological consequencesAntioxid Redox Signal5577582PubMedCrossRefGoogle Scholar
  65. Su, H, Deng, G, Cotman, CW 1997Neuronal DNA damage precedes tangle formation and is associated with up-regulation of nitrotyrosine in Alzheimer’s disease brainBrain Res774193199PubMedCrossRefGoogle Scholar
  66. Vina, J, Lloret, A, Ortí, R, Alonso, D 2004Molecular bases of the treatment of Alzheimer’s disease with antioxidants: prevention of oxidative stressMol Aspects Med25117123PubMedCrossRefGoogle Scholar
  67. Wang, J, Xiong, S, Xie, C, Markesbery, WR, Lovell, MA 2005Increased oxidative damage in nuclear and mitochondrial DNA in Alzheimer’s diseaseJ Neurochem93953962PubMedCrossRefGoogle Scholar
  68. Yan, LJ, Levine, RL, Sohal, RS 1997Oxidative damage during aging targets mitochondrial aconitaseProc Natl Acad Sci USA94111968111972CrossRefGoogle Scholar
  69. Zhu, X, Raina, AK, Lee, H, Casadesus, G, Smith, MA, Perry, G 2004Oxidative stress signalling in Alzheimer’s diseaseBrain Res10003239PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • M. C. Polidori
    • 1
  • H. R. Griffiths
    • 2
  • E. Mariani
    • 3
  • P. Mecocci
    • 3
  1. 1.Institute of Biochemistry and Molecular Biology IHeinrich-Heine UniversityDüsseldorfGermany
  2. 2.Life and Health SciencesAston UniversityAston TriangleBirmingham, U.K.
  3. 3.Institute of Gerontology and GeriatricsUniversity of PerugiaPerugiaItaly

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