Acta Neuropathologica

, Volume 118, Issue 1, pp 131–150 | Cite as

Oxidatively modified proteins in Alzheimer’s disease (AD), mild cognitive impairment and animal models of AD: role of Abeta in pathogenesis

  • Rukhsana Sultana
  • Marzia Perluigi
  • D. Allan Butterfield


Oxidative stress has been implicated in the pathogenesis of a number of diseases including Alzheimer’s disease (AD). The oxidative stress hypothesis of AD pathogenesis, in part, is based on β-amyloid peptide (Aβ)-induced oxidative stress in both in vitro and in vivo studies. Oxidative modification of the protein may induce structural changes in a protein that might lead to its functional impairment. A number of oxidatively modified brain proteins were identified using redox proteomics in AD, mild cognitive impairment (MCI) and Aβ models of AD, which support a role of Aβ in the alteration of a number of biochemical and cellular processes such as energy metabolism, protein degradation, synaptic function, neuritic growth, neurotransmission, cellular defense system, long term potentiation involved in formation of memory, etc. All the redox proteomics-identified brain proteins fit well with the appearance of the three histopathological hallmarks of AD, i.e., synapse loss, amyloid plaque formation and neurofibrillary tangle formation and suggest a direct or indirect association of the identified proteins with the pathological and/or biochemical alterations in AD. Further, Aβ models of AD strongly support the notion that oxidative stress induced by Aβ may be a driving force in AD pathogenesis. Studies conducted on arguably the earliest stage of AD, MCI, may elucidate the mechanism(s) leading to AD pathogenesis by identifying early markers of the disease, and to develop therapeutic strategies to slow or prevent the progression of AD. In this review, we summarized our findings of redox proteomics identified oxidatively modified proteins in AD, MCI and AD models.


Oxidative stress Alzheimer’s disease Mild cognitive impairment Protein oxidation 4-Hydroxy 2-trans-nonenal 3-Nitrotyrosine Redox proteomics 



This work was supported in part by grants from NIH to D.A.B. [AG-05119; AG-10836; AG-029839].


  1. 1.
    Abdul HM, Calabrese V, Calvani M, Butterfield DA (2006) Acetyl-l-carnitine-induced up-regulation of heat shock proteins protects cortical neurons against amyloid-beta peptide 1–42-mediated oxidative stress and neurotoxicity: implications for Alzheimer’s disease. J Neurosci Res 84:398–408. doi: 10.1002/jnr.20877 PubMedGoogle Scholar
  2. 2.
    Aksenova M, Butterfield DA, Zhang SX, Underwood M, Geddes JW (2002) Increased protein oxidation and decreased creatine kinase BB expression and activity after spinal cord contusion injury. J Neurotrauma 19:491–502. doi: 10.1089/08977150252932433 PubMedGoogle Scholar
  3. 3.
    Anantharaman M, Tangpong J, Keller JN, Murphy MP, Markesbery WR, Kiningham KK, St Clair DK (2006) Beta-amyloid mediated nitration of manganese superoxide dismutase: implication for oxidative stress in a APPNLH/NLH X PS-1P264L/P264L double knock-in mouse model of Alzheimer’s disease. Am J Pathol 168:1608–1618. doi: 10.2353/ajpath.2006.051223 PubMedGoogle Scholar
  4. 4.
    Ansari MA, Joshi G, Huang Q, Opii WO, Abdul HM, Sultana R, Butterfield DA (2006) In vivo administration of D609 leads to protection of subsequently isolated gerbil brain mitochondria subjected to in vitro oxidative stress induced by amyloid beta-peptide and other oxidative stressors: relevance to Alzheimer’s disease and other oxidative stress-related neurodegenerative disorders. Free Radic Biol Med 41:1694–1703. doi: 10.1016/j.freeradbiomed.2006.09.002 PubMedGoogle Scholar
  5. 5.
    Bader Lange ML, Cenini G, Piroddi M, Abdul HM, Sultana R, Galli F, Memo M, Butterfield DA (2008) Loss of phospholipid asymmetry and elevated brain apoptotic protein levels in subjects with amnestic mild cognitive impairment and Alzheimer disease. Neurobiol Dis 29:456–464PubMedCrossRefGoogle Scholar
  6. 6.
    Beckman JS (1996) Oxidative damage and tyrosine nitration from peroxynitrite. Chem Res Toxicol 9:836–844. doi: 10.1021/tx9501445 PubMedGoogle Scholar
  7. 7.
    Biroccio A, Del Boccio P, Panella M, Bernardini S, Di Ilio C, Gambi D, Stanzione P, Sacchetta P, Bernardi G, Martorana A, Federici G, Stefani A, Urbani A (2006) Differential post-translational modifications of transthyretin in Alzheimer’s disease: a study of the cerebral spinal fluid. Proteomics 6:2305–2313. doi: 10.1002/pmic.200500285 PubMedGoogle Scholar
  8. 8.
    Boyd-Kimball D, Castegna A, Sultana R, Poon HF, Petroze R, Lynn BC, Klein JB, Butterfield DA (2005) Proteomic identification of proteins oxidized by Abeta(1–42) in synaptosomes: implications for Alzheimer’s disease. Brain Res 1044:206–215. doi: 10.1016/j.brainres.2005.02.086 PubMedGoogle Scholar
  9. 9.
    Boyd-Kimball D, Poon HF, Lynn BC, Cai J, Pierce WM Jr, Klein JB, Ferguson J, Link CD, Butterfield DA (2006) Proteomic identification of proteins specifically oxidized in Caenorhabditis elegans expressing human Abeta(1–42): implications for Alzheimer’s disease. Neurobiol Aging 27:1239–1249. doi: 10.1016/j.neurobiolaging.2005.07.001 PubMedGoogle Scholar
  10. 10.
    Boyd-Kimball D, Sultana R, Mohmmad-Abdul H, Butterfield DA (2005) Neurotoxicity and oxidative stress in D1M-substituted Alzheimer’s A beta(1–42): relevance to N-terminal methionine chemistry in small model peptides. Peptides 26:665–673. doi: 10.1016/j.peptides.2004.11.001 PubMedGoogle Scholar
  11. 11.
    Boyd-Kimball D, Sultana R, Poon HF, Lynn BC, Casamenti F, Pepeu G, Klein JB, Butterfield DA (2005) Proteomic identification of proteins specifically oxidized by intracerebral injection of amyloid beta-peptide (1–42) into rat brain: implications for Alzheimer’s disease. Neuroscience 132:313–324. doi: 10.1016/j.neuroscience.2004.12.022 PubMedGoogle Scholar
  12. 12.
    Boyd-Kimball D, Sultana R, Poon HF, Mohmmad-Abdul H, Lynn BC, Klein JB, Butterfield DA (2005) Gamma-glutamylcysteine ethyl ester protection of proteins from Abeta(1–42)-mediated oxidative stress in neuronal cell culture: a proteomics approach. J Neurosci Res 79:707–713. doi: 10.1002/jnr.20393 PubMedGoogle Scholar
  13. 13.
    Brunelle P, Rauk A (2002) The radical model of Alzheimer’s disease: specific recognition of Gly29 and Gly33 by Met35 in a beta-sheet model of Abeta: an ONIOM study. J Alzheimers Dis 4:283–289PubMedGoogle Scholar
  14. 14.
    Butterfield DA (2002) Amyloid beta-peptide (1–42)-induced oxidative stress and neurotoxicity: implications for neurodegeneration in Alzheimer’s disease brain. A review. Free Radic Res 36:1307–1313. doi: 10.1080/1071576021000049890 PubMedGoogle Scholar
  15. 15.
    Butterfield DA (1997) beta-Amyloid-associated free radical oxidative stress and neurotoxicity: implications for Alzheimer’s disease. Chem Res Toxicol 10:495–506. doi: 10.1021/tx960130e PubMedGoogle Scholar
  16. 16.
    Butterfield DA, Abdul HM, Newman S, Reed T (2006) Redox proteomics in some age-related neurodegenerative disorders or models thereof. NeuroRx 3:344–357. doi: 10.1016/j.nurx.2006.05.003 PubMedGoogle Scholar
  17. 17.
    Butterfield DA, Boyd-Kimball D (2004) Amyloid beta-peptide(1–42) contributes to the oxidative stress and neurodegeneration found in Alzheimer disease brain. Brain Pathol 14:426–432PubMedGoogle Scholar
  18. 18.
    Butterfield DA, Boyd-Kimball D (2005) The critical role of methionine 35 in Alzheimer’s amyloid beta-peptide (1–42)-induced oxidative stress and neurotoxicity. Biochim Biophys Acta 1703:149–156PubMedGoogle Scholar
  19. 19.
    Butterfield DA, Boyd-Kimball D, Castegna A (2003) Proteomics in Alzheimer’s disease: insights into potential mechanisms of neurodegeneration. J Neurochem 86:1313–1327. doi: 10.1046/j.1471-4159.2003.01948.x PubMedGoogle Scholar
  20. 20.
    Butterfield DA, Castegna A, Lauderback CM, Drake J (2002) Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer’s disease brain contribute to neuronal death. Neurobiol Aging 23:655–664. doi: 10.1016/S0197-4580(01)00340-2 PubMedGoogle Scholar
  21. 21.
    Butterfield DA, Drake J, Pocernich C, Castegna A (2001) Evidence of oxidative damage in Alzheimer’s disease brain: central role for amyloid beta-peptide. Trends Mol Med 7:548–554. doi: 10.1016/S1471-4914(01)02173-6 PubMedGoogle Scholar
  22. 22.
    Butterfield DA, Gnjec A, Poon HF, Castegna A, Pierce WM, Klein JB, Martins RN (2006) Redox proteomics identification of oxidatively modified brain proteins in inherited Alzheimer’s disease: an initial assessment. J Alzheimers Dis 10:391–397PubMedGoogle Scholar
  23. 23.
    Butterfield DA, Hensley K, Cole P, Subramaniam R, Aksenov M, Aksenova M, Bummer PM, Haley BE, Carney JM (1997) Oxidatively induced structural alteration of glutamine synthetase assessed by analysis of spin label incorporation kinetics: relevance to Alzheimer’s disease. J Neurochem 68:2451–2457PubMedGoogle Scholar
  24. 24.
    Butterfield DA, Kanski J (2001) Brain protein oxidation in age-related neurodegenerative disorders that are associated with aggregated proteins. Mech Ageing Dev 122:945–962. doi: 10.1016/S0047-6374(01)00249-4 PubMedGoogle Scholar
  25. 25.
    Butterfield DA, Lauderback CM (2002) Lipid peroxidation and protein oxidation in Alzheimer’s disease brain: potential causes and consequences involving amyloid beta-peptide-associated free radical oxidative stress. Free Radic Biol Med 32:1050–1060. doi: 10.1016/S0891-5849(02)00794-3 PubMedGoogle Scholar
  26. 26.
    Butterfield DA, Mohmmad-Abdul H, Opii W, Newman SF, Joshi G, Ansari MA, Sultana R (2006) Role of Pin1 in Alzheimer’s disease. J Neurochem 98:1699–1706. doi: 10.1111/j.1471-4159.2006.03995.x Google Scholar
  27. 27.
    Butterfield DA, Poon HF, St Clair D, Keller JN, Pierce WM, Klein JB, Markesbery WR (2006) Redox proteomics identification of oxidatively modified hippocampal proteins in mild cognitive impairment: insights into the development of Alzheimer’s disease. Neurobiol Dis 22:223–232. doi: 10.1016/j.nbd.2005.11.002 PubMedGoogle Scholar
  28. 28.
    Butterfield DA, Reed T, Newman SF, Sultana R (2007) Roles of amyloid beta-peptide-associated oxidative stress and brain protein modifications in the pathogenesis of Alzheimer’s disease and mild cognitive impairment. Free Radic Biol Med 43:658–677. doi: 10.1016/j.freeradbiomed.2007.05.037 PubMedGoogle Scholar
  29. 29.
    Butterfield DA, Reed T, Perluigi M, De Marco C, Coccia R, Cini C, Sultana R (2006) Elevated protein-bound levels of the lipid peroxidation product, 4-hydroxy-2-nonenal, in brain from persons with mild cognitive impairment. Neurosci Lett 397:170–173. doi: 10.1016/j.neulet.2005.12.017 PubMedGoogle Scholar
  30. 30.
    Butterfield DA, Stadtman ER (1997) Protein Oxidation processes in aging brain. Adv Cell Aging Gerontol 2:161–191. doi: 10.1016/S1566-3124(08)60057-7 Google Scholar
  31. 31.
    Carney JM, Starke-Reed PE, Oliver CN, Landum RW, Cheng MS, Wu JF, Floyd RA (1991) Reversal of age-related increase in brain protein oxidation, decrease in enzyme activity, and loss in temporal and spatial memory by chronic administration of the spin-trapping compound N-tert-butyl-alpha-phenylnitrone. Proc Natl Acad Sci USA 88:3633–3636. doi: 10.1073/pnas.88.9.3633 PubMedGoogle Scholar
  32. 32.
    Castegna A, Aksenov M, Aksenova M, Thongboonkerd V, Klein JB, Pierce WM, Booze R, Markesbery WR, Butterfield DA (2002) Proteomic identification of oxidatively modified proteins in Alzheimer’s disease brain. Part I: creatine kinase BB, glutamine synthase, and ubiquitin carboxy-terminal hydrolase L-1. Free Radic Biol Med 33:562–571. doi: 10.1016/S0891-5849(02)00914-0 PubMedGoogle Scholar
  33. 33.
    Castegna A, Aksenov M, Thongboonkerd V, Klein JB, Pierce WM, Booze R, Markesbery WR, Butterfield DA (2002) Proteomic identification of oxidatively modified proteins in Alzheimer’s disease brain. Part II: dihydropyrimidinase-related protein 2, alpha-enolase and heat shock cognate 71. J Neurochem 82:1524–1532. doi: 10.1046/j.1471-4159.2002.01103.x PubMedGoogle Scholar
  34. 34.
    Castegna A, Lauderback CM, Mohmmad-Abdul H, Butterfield DA (2004) Modulation of phospholipid asymmetry in synaptosomal membranes by the lipid peroxidation products, 4-hydroxynonenal and acrolein: implications for Alzheimer’s disease. Brain Res 1004:193–197. doi: 10.1016/j.brainres.2004.01.036 PubMedGoogle Scholar
  35. 35.
    Castegna A, Thongboonkerd V, Klein JB, Lynn B, Markesbery WR, Butterfield DA (2003) Proteomic identification of nitrated proteins in Alzheimer’s disease brain. J Neurochem 85:1394–1401. doi: 10.1046/j.1471-4159.2003.01786.x PubMedGoogle Scholar
  36. 36.
    Cenini G, Sultana R, Memo M, Butterfield DA (2008) Elevated levels of pro-apoptotic p53 and its oxidative modification by the lipid peroxidation product, HNE, in brain from subjects with amnestic mild cognitive impairment and Alzheimer’s disease. J Cell Mol Med 12:987–994. doi: 10.1111/j.1582-4934.2008.00163.x PubMedGoogle Scholar
  37. 37.
    Chang RC, Wong AK, Ng HK, Hugon J (2002) Phosphorylation of eukaryotic initiation factor-2alpha (eIF2alpha) is associated with neuronal degeneration in Alzheimer’s disease. NeuroReport 13:2429–2432. doi: 10.1097/00001756-200212200-00011 PubMedGoogle Scholar
  38. 38.
    Chertkow H, Bergman H, Schipper HM, Gauthier S, Bouchard R, Fontaine S, Clarfield AM (2001) Assessment of suspected dementia. Can J Neurol Sci 28(Suppl 1):S28–S41PubMedGoogle Scholar
  39. 39.
    Choi J, Levey AI, Weintraub ST, Rees HD, Gearing M, Chin LS, Li L (2004) Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson’s and Alzheimer’s diseases. J Biol Chem 279:13256–13264. doi: 10.1074/jbc.M314124200 PubMedGoogle Scholar
  40. 40.
    Choi J, Rees HD, Weintraub ST, Levey AI, Chin LS, Li L (2005) Oxidative modifications and aggregation of Cu, Zn-superoxide dismutase associated with Alzheimer and Parkinson diseases. J Biol Chem 280:11648–11655. doi: 10.1074/jbc.M414327200 PubMedGoogle Scholar
  41. 41.
    Clementi ME, Pezzotti M, Orsini F, Sampaolese B, Mezzogori D, Grassi C, Giardina B, Misiti F (2006) Alzheimer’s amyloid beta-peptide (1–42) induces cell death in human neuroblastoma via bax/bcl-2 ratio increase: an intriguing role for methionine 35. Biochem Biophys Res Commun 342:206–213. doi: 10.1016/j.bbrc.2006.01.137 PubMedGoogle Scholar
  42. 42.
    Coleman PD, Flood DG (1987) Neuron numbers and dendritic extent in normal aging and Alzheimer’s disease. Neurobiol Aging 8:521–545. doi: 10.1016/0197-4580(87)90127-8 PubMedGoogle Scholar
  43. 43.
    Cotman CW, Head E, Muggenburg BA, Zicker S, Milgram NW (2002) Brain aging in the canine: a diet enriched in antioxidants reduces cognitive dysfunction. Neurobiol Aging 23:809–818. doi: 10.1016/S0197-4580(02)00073-8 PubMedGoogle Scholar
  44. 44.
    Coyle JT, Price DL, DeLong MR (1983) Alzheimer’s disease: a disorder of cortical cholinergic innervation. Science 219:1184–1190. doi: 10.1126/science.6338589 PubMedGoogle Scholar
  45. 45.
    Crouch PJ, Barnham KJ, Duce JA, Blake RE, Masters CL, Trounce IA (2006) Copper-dependent inhibition of cytochrome c oxidase by Abeta(1–42) requires reduced methionine at residue 35 of the Abeta peptide. J Neurochem 99:226–236. doi: 10.1111/j.1471-4159.2006.04050.x PubMedGoogle Scholar
  46. 46.
    Cummings BJ, Head E, Ruehl W, Milgram NW, Cotman CW (1996) The canine as an animal model of human aging and dementia. Neurobiol Aging 17:259–268. doi: 10.1016/0197-4580(95)02060-8 PubMedGoogle Scholar
  47. 47.
    Cutler RG, Kelly J, Storie K, Pedersen WA, Tammara A, Hatanpaa K, Troncoso JC, Mattson MP (2004) Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer’s disease. Proc Natl Acad Sci USA 101:2070–2075. doi: 10.1073/pnas.0305799101 PubMedGoogle Scholar
  48. 48.
    Dalle-Donne I, Scaloni A, Butterfield DA (2006) Redox proteomics: from protein modifications to cellular dysfunction and diseases. Wiley, HobokenGoogle Scholar
  49. 49.
    Dalle-Donne I, Scaloni A, Giustarini D, Cavarra E, Tell G, Lungarella G, Colombo R, Rossi R, Milzani A (2005) Proteins as biomarkers of oxidative/nitrosative stress in diseases: the contribution of redox proteomics. Mass Spectrom Rev 24:55–99. doi: 10.1002/mas.20006 PubMedGoogle Scholar
  50. 50.
    Davies MJ, Fu S, Wang H, Dean RT (1999) Stable markers of oxidant damage to proteins and their application in the study of human disease. Free Radic Biol Med 27:1151–1163. doi: 10.1016/S0891-5849(99)00206-3 PubMedGoogle Scholar
  51. 51.
    Demuro A, Mina E, Kayed R, Milton SC, Parker I, Glabe CG (2005) Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. J Biol Chem 280:17294–17300. doi: 10.1074/jbc.M500997200 PubMedGoogle Scholar
  52. 52.
    Ding Q, Markesbery WR, Cecarini V, Keller JN (2006) Decreased RNA, and increased RNA oxidation, in ribosomes from early Alzheimer’s disease. Neurochem Res 31:705–710. doi: 10.1007/s11064-006-9071-5 PubMedGoogle Scholar
  53. 53.
    Ding Q, Markesbery WR, Chen Q, Li F, Keller JN (2005) Ribosome dysfunction is an early event in Alzheimer’s disease. J Neurosci 25:9171–9175. doi: 10.1523/JNEUROSCI.3040-05.2005 PubMedGoogle Scholar
  54. 54.
    Drake J, Link CD, Butterfield DA (2003) Oxidative stress precedes fibrillar deposition of Alzheimer’s disease amyloid beta-peptide (1–42) in a transgenic Caenorhabditis elegans model. Neurobiol Aging 24:415–420. doi: 10.1016/S0197-4580(02)00225-7 PubMedGoogle Scholar
  55. 55.
    Dyrks T, Dyrks E, Hartmann T, Masters C, Beyreuther K (1992) Amyloidogenicity of beta A4 and beta A4-bearing amyloid protein precursor fragments by metal-catalyzed oxidation. J Biol Chem 267:18210–18217PubMedGoogle Scholar
  56. 56.
    Esterbauer H, Schaur RJ, Zollner H (1991) Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med 11:81–128. doi: 10.1016/0891-5849(91)90192-6 PubMedGoogle Scholar
  57. 57.
    Farooqui AA, Horrocks LA (2006) Phospholipase A2-generated lipid mediators in the brain: the good, the bad, and the ugly. Neuroscientist 12:245–260. doi: 10.1177/1073858405285923 PubMedGoogle Scholar
  58. 58.
    Ferl RJ (1996) 14-3-3 proteins and signal transduction. Annu Rev Plant Physiol Plant Mol Biol 47:49–73. doi: 10.1146/annurev.arplant.47.1.49 PubMedGoogle Scholar
  59. 59.
    Fisher A (2008) Cholinergic treatments with emphasis on m1 muscarinic agonists as potential disease-modifying agents for Alzheimer’s disease. Neurotherapeutics 5:433–442. doi: 10.1016/j.nurt.2008.05.002 PubMedGoogle Scholar
  60. 60.
    Fisher A (1999) Muscarinic receptor agonists in Alzheimer’s disease: more than just symptomatic treatment? CNS Drugs 123:197–214. doi: 10.2165/00023210-199912030-00004 Google Scholar
  61. 61.
    Geula C, Nagykery N, Nicholas A, Wu CK (2008) Cholinergic neuronal and axonal abnormalities are present early in aging and in Alzheimer disease. J Neuropathol Exp Neurol 67:309–318. doi: 10.1097/NEN.0b013e31816a1df3 PubMedGoogle Scholar
  62. 62.
    Giovannini MG, Scali C, Prosperi C, Bellucci A, Vannucchi MG, Rosi S, Pepeu G, Casamenti F (2002) Beta-amyloid-induced inflammation and cholinergic hypofunction in the rat brain in vivo: involvement of the p38MAPK pathway. Neurobiol Dis 11:257–274. doi: 10.1006/nbdi.2002.0538 PubMedGoogle Scholar
  63. 63.
    Gong B, Cao Z, Zheng P, Vitolo OV, Liu S, Staniszewski A, Moolman D, Zhang H, Shelanski M, Arancio O (2006) Ubiquitin hydrolase Uch-L1 rescues beta-amyloid-induced decreases in synaptic function and contextual memory. Cell 126:775–788. doi: 10.1016/j.cell.2006.06.046 PubMedGoogle Scholar
  64. 64.
    Gothel SF, Marahiel MA (1999) Peptidyl-prolyl cis-trans isomerases, a superfamily of ubiquitous folding catalysts. Cell Mol Life Sci 55:423–436. doi: 10.1007/s000180050299 PubMedGoogle Scholar
  65. 65.
    Guidi I, Galimberti D, Lonati S, Novembrino C, Bamonti F, Tiriticco M, Fenoglio C, Venturelli E, Baron P, Bresolin N, Scarpini E (2006) Oxidative imbalance in patients with mild cognitive impairment and Alzheimer’s disease. Neurobiol Aging 27:262–269. doi: 10.1016/j.neurobiolaging.2005.01.001 PubMedGoogle Scholar
  66. 66.
    Halliwell B (2006) Oxidative stress and neurodegeneration: where are we now? J Neurochem 97:1634–1658. doi: 10.1111/j.1471-4159.2006.03907.x PubMedGoogle Scholar
  67. 67.
    Hamdane M, Dourlen P, Bretteville A, Sambo AV, Ferreira S, Ando K, Kerdraon O, Begard S, Geay L, Lippens G, Sergeant N, Delacourte A, Maurage CA, Galas MC, Buee L (2006) Pin1 allows for differential Tau dephosphorylation in neuronal cells. Mol Cell Neurosci 32:155–160. doi: 10.1016/j.mcn.2006.03.006 PubMedGoogle Scholar
  68. 68.
    Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356. doi: 10.1126/science.1072994 PubMedGoogle Scholar
  69. 69.
    Head E, Callahan H, Muggenburg BA, Cotman CW, Milgram NW (1998) Visual-discrimination learning ability and beta-amyloid accumulation in the dog. Neurobiol Aging 19:415–425. doi: 10.1016/S0197-4580(98)00084-0 PubMedGoogle Scholar
  70. 70.
    Head E, Torp R (2002) Insights into Abeta and presenilin from a canine model of human brain aging. Neurobiol Dis 9:1–10. doi: 10.1006/nbdi.2002.0476 PubMedGoogle Scholar
  71. 71.
    Hensley K, Hall N, Subramaniam R, Cole P, Harris M, Aksenov M, Aksenova M, Gabbita SP, Wu JF, Carney JM et al (1995) Brain regional correspondence between Alzheimer’s disease histopathology and biomarkers of protein oxidation. J Neurochem 65:2146–2156PubMedGoogle Scholar
  72. 72.
    Holzer M, Gartner U, Stobe A, Hartig W, Gruschka H, Bruckner MK, Arendt T (2002) Inverse association of Pin1 and tau accumulation in Alzheimer’s disease hippocampus. Acta Neuropathol 104:471–481PubMedGoogle Scholar
  73. 73.
    Ischiropoulos H, al-Mehdi AB (1995) Peroxynitrite-mediated oxidative protein modifications. FEBS Lett 364:279–282. doi: 10.1016/0014-5793(95)00307-U PubMedGoogle Scholar
  74. 74.
    Joshi G, Perluigi M, Sultana R, Agrippino R, Calabrese V, Butterfield DA (2006) In vivo protection of synaptosomes by ferulic acid ethyl ester (FAEE) from oxidative stress mediated by 2,2-azobis(2-amidino-propane)dihydrochloride (AAPH) or Fe(2+)/H(2)O(2): insight into mechanisms of neuroprotection and relevance to oxidative stress-related neurodegenerative disorders. Neurochem Int 48:318–327. doi: 10.1016/j.neuint.2005.11.006 PubMedGoogle Scholar
  75. 75.
    Joshi G, Sultana R, Perluigi M, Allan Butterfield D (2005) In vivo protection of synaptosomes from oxidative stress mediated by Fe2+/H2O2 or 2, 2-azobis-(2-amidinopropane) dihydrochloride by the glutathione mimetic tricyclodecan-9-yl-xanthogenate. Free Radic Biol Med 38:1023–1031. doi: 10.1016/j.freeradbiomed.2004.12.027 PubMedGoogle Scholar
  76. 76.
    Kanski J, Aksenova M, Schoneich C, Butterfield DA (2002) Substitution of isoleucine-31 by helical-breaking proline abolishes oxidative stress and neurotoxic properties of Alzheimer’s amyloid beta-peptide. Free Radic Biol Med 32:1205–1211. doi: 10.1016/S0891-5849(02)00821-3 PubMedGoogle Scholar
  77. 77.
    Kanski J, Varadarajan S, Aksenova M, Butterfield DA (2002) Role of glycine-33 and methionine-35 in Alzheimer’s amyloid beta-peptide 1–42-associated oxidative stress and neurotoxicity. Biochim Biophys Acta 1586:190–198PubMedGoogle Scholar
  78. 78.
    Keller JN, Hanni KB, Markesbery WR (2000) Impaired proteasome function in Alzheimer’s disease. J Neurochem 75:436–439. doi: 10.1046/j.1471-4159.2000.0750436.x PubMedGoogle Scholar
  79. 79.
    Keller JN, Schmitt FA, Scheff SW, Ding Q, Chen Q, Butterfield DA, Markesbery WR (2005) Evidence of increased oxidative damage in subjects with mild cognitive impairment. Neurology 64:1152–1156PubMedGoogle Scholar
  80. 80.
    Korolainen MA, Goldsteins G, Alafuzoff I, Koistinaho J, Pirttila T (2002) Proteomic analysis of protein oxidation in Alzheimer’s disease brain. Electrophoresis 23:3428–3433. doi: 10.1002/1522-2683(200210)23:19<3428::AID-ELPS3428>3.0.CO;2-5 PubMedGoogle Scholar
  81. 81.
    Korolainen MA, Goldsteins G, Nyman TA, Alafuzoff I, Koistinaho J, Pirttila T (2006) Oxidative modification of proteins in the frontal cortex of Alzheimer’s disease brain. Neurobiol Aging 27:42–53. doi: 10.1016/j.neurobiolaging.2004.11.010 PubMedGoogle Scholar
  82. 82.
    Lafon-Cazal M, Fagni L, Guiraud MJ, Mary S, Lerner-Natoli M, Pin JP, Shigemoto R, Bockaert J (1999) mGluR7-like metabotropic glutamate receptors inhibit NMDA-mediated excitotoxicity in cultured mouse cerebellar granule neurons. Eur J NeuroSci 11:663–672. doi: 10.1046/j.1460-9568.1999.00475.x PubMedGoogle Scholar
  83. 83.
    Lahiri DK, Ge YW, Maloney B, Wavrant-De Vrieze F, Hardy J (2005) Characterization of two APP gene promoter polymorphisms that appear to influence risk of late-onset Alzheimer’s disease. Neurobiol Aging 26:1329–1341. doi: 10.1016/j.neurobiolaging.2004.11.005 PubMedGoogle Scholar
  84. 84.
    Lambert JC, Mann DM, Harris JM, Chartier-Harlin MC, Cumming A, Coates J, Lemmon H, StClair D, Iwatsubo T, Lendon C (2001) The −48 C/T polymorphism in the presenilin 1 promoter is associated with an increased risk of developing Alzheimer’s disease and an increased Abeta load in brain. J Med Genet 38:353–355. doi: 10.1136/jmg.38.6.353 PubMedGoogle Scholar
  85. 85.
    Lauderback CM, Hackett JM, Huang FF, Keller JN, Szweda LI, Markesbery WR, Butterfield DA (2001) The glial glutamate transporter, GLT-1, is oxidatively modified by 4-hydroxy-2-nonenal in the Alzheimer’s disease brain: the role of Abeta1–42. J Neurochem 78:413–416. doi: 10.1046/j.1471-4159.2001.00451.x PubMedGoogle Scholar
  86. 86.
    Layfield R, Fergusson J, Aitken A, Lowe J, Landon M, Mayer RJ (1996) Neurofibrillary tangles of Alzheimer’s disease brains contain 14-3-3 proteins. Neurosci Lett 209:57–60. doi: 10.1016/0304-3940(96)12598-2 PubMedGoogle Scholar
  87. 87.
    Levine RL, Williams JA, Stadtman ER, Shacter E (1994) Carbonyl assays for determination of oxidatively modified proteins. Methods Enzymol 233:346–357. doi: 10.1016/S0076-6879(94)33040-9 PubMedGoogle Scholar
  88. 88.
    Levy-Lahad E, Lahad A, Wijsman EM, Bird TD, Schellenberg GD (1995) Apolipoprotein E genotypes and age of onset in early-onset familial Alzheimer’s disease. Ann Neurol 38:678–680. doi: 10.1002/ana.410380420 PubMedGoogle Scholar
  89. 89.
    Li X, An WL, Alafuzoff I, Soininen H, Winblad B, Pei JJ (2004) Phosphorylated eukaryotic translation factor 4E is elevated in Alzheimer brain. NeuroReport 15:2237–2240. doi: 10.1097/00001756-200410050-00019 PubMedGoogle Scholar
  90. 90.
    Ling M, Merante F, Chen HS, Duff C, Duncan AM, Robinson BH (1997) The human mitochondrial elongation factor tu (EF-Tu) gene: cDNA sequence, genomic localization, genomic structure, and identification of a pseudogene. Gene 197:325–336. doi: 10.1016/S0378-1119(97)00279-5 PubMedGoogle Scholar
  91. 91.
    Link CD (2006) C. elegans models of age-associated neurodegenerative diseases: lessons from transgenic worm models of Alzheimer’s disease. Exp Gerontol 41:1007–1013. doi: 10.1016/j.exger.2006.06.059 PubMedGoogle Scholar
  92. 92.
    Link CD (1995) Expression of human beta-amyloid peptide in transgenic Caenorhabditis elegans. Proc Natl Acad Sci USA 92:9368–9372. doi: 10.1073/pnas.92.20.9368 PubMedGoogle Scholar
  93. 93.
    Liou YC, Sun A, Ryo A, Zhou XZ, Yu ZX, Huang HK, Uchida T, Bronson R, Bing G, Li X, Hunter T, Lu KP (2003) Role of the prolyl isomerase Pin1 in protecting against age-dependent neurodegeneration. Nature 424:556–561. doi: 10.1038/nature01832 PubMedGoogle Scholar
  94. 94.
    Lledo PM, Zhang X, Sudhof TC, Malenka RC, Nicoll RA (1998) Postsynaptic membrane fusion and long-term potentiation. Science 279:399–403. doi: 10.1126/science.279.5349.399 PubMedGoogle Scholar
  95. 95.
    Lovell MA, Markesbery WR (2007) Oxidative damage in mild cognitive impairment and early Alzheimer’s disease. J Neurosci Res 85:3036–3040. doi: 10.1002/jnr.21346 PubMedGoogle Scholar
  96. 96.
    Lovell MA, Markesbery WR (2001) Ratio of 8-hydroxyguanine in intact DNA to free 8-hydroxyguanine is increased in Alzheimer disease ventricular cerebrospinal fluid. Arch Neurol 58:392–396. doi: 10.1001/archneur.58.3.392 PubMedGoogle Scholar
  97. 97.
    Lovell MA, Xie C, Markesbery WR (2001) Acrolein is increased in Alzheimer’s disease brain and is toxic to primary hippocampal cultures. Neurobiol Aging 22:187–194. doi: 10.1016/S0197-4580(00)00235-9 PubMedGoogle Scholar
  98. 98.
    Lu KP, Hanes SD, Hunter T (1996) A human peptidyl-prolyl isomerase essential for regulation of mitosis. Nature 380:544–547. doi: 10.1038/380544a0 PubMedGoogle Scholar
  99. 99.
    Lubec G, Nonaka M, Krapfenbauer K, Gratzer M, Cairns N, Fountoulakis M (1999) Expression of the dihydropyrimidinase related protein 2 (DRP-2) in Down syndrome and Alzheimer’s disease brain is downregulated at the mRNA and dysregulated at the protein level. J Neural Transm Suppl 57:161–177PubMedGoogle Scholar
  100. 100.
    Marin R, Ramirez CM, Gonzalez M, Gonzalez-Munoz E, Zorzano A, Camps M, Alonso R, Diaz M (2007) Voltage-dependent anion channel (VDAC) participates in amyloid beta-induced toxicity and interacts with plasma membrane estrogen receptor alpha in septal and hippocampal neurons. Mol Membr Biol 24:148–160. doi: 10.1080/09687860601055559 PubMedGoogle Scholar
  101. 101.
    Mark RJ, Lovell MA, Markesbery WR, Uchida K, Mattson MP (1997) A role for 4-hydroxynonenal, an aldehydic product of lipid peroxidation, in disruption of ion homeostasis and neuronal death induced by amyloid beta-peptide. J Neurochem 68:255–264PubMedGoogle Scholar
  102. 102.
    Markesbery WR (1997) Oxidative stress hypothesis in Alzheimer’s disease. Free Radic Biol Med 23:134–147. doi: 10.1016/S0891-5849(96)00629-6 PubMedGoogle Scholar
  103. 103.
    Markesbery WR, Lovell MA (1998) Four-hydroxynonenal, a product of lipid peroxidation, is increased in the brain in Alzheimer’s disease. Neurobiol Aging 19:33–36. doi: 10.1016/S0197-4580(98)00009-8 PubMedGoogle Scholar
  104. 104.
    Mattson MP, Partin J, Begley JG (1998) Amyloid beta-peptide induces apoptosis-related events in synapses and dendrites. Brain Res 807:167–176. doi: 10.1016/S0006-8993(98)00763-X PubMedGoogle Scholar
  105. 105.
    Mazzola JL, Sirover MA (2001) Reduction of glyceraldehyde-3-phosphate dehydrogenase activity in Alzheimer’s disease and in Huntington’s disease fibroblasts. J Neurochem 76:442–449. doi: 10.1046/j.1471-4159.2001.00033.x PubMedGoogle Scholar
  106. 106.
    Meier-Ruge W, Iwangoff P, Reichlmeier K (1984) Neurochemical enzyme changes in Alzheimer’s and Pick’s disease. Arch Gerontol Geriatr 3:161–165. doi: 10.1016/0167-4943(84)90007-4 PubMedGoogle Scholar
  107. 107.
    Mello CF, Sultana R, Piroddi M, Cai J, Pierce WM, Klein JB, Butterfield DA (2007) Acrolein induces selective protein carbonylation in synaptosomes. Neuroscience 147:674–679. doi: 10.1016/j.neuroscience.2007.04.003 PubMedGoogle Scholar
  108. 108.
    Milgram NW, Head E, Zicker SC, Ikeda-Douglas CJ, Murphey H, Muggenburg B, Siwak C, Tapp D, Cotman CW (2005) Learning ability in aged beagle dogs is preserved by behavioral enrichment and dietary fortification: a two-year longitudinal study. Neurobiol Aging 26:77–90. doi: 10.1016/j.neurobiolaging.2004.02.014 PubMedGoogle Scholar
  109. 109.
    Milgram NW, Zicker SC, Head E, Muggenburg BA, Murphey H, Ikeda-Douglas CJ, Cotman CW (2002) Dietary enrichment counteracts age-associated cognitive dysfunction in canines. Neurobiol Aging 23:737–745. doi: 10.1016/S0197-4580(02)00020-9 PubMedGoogle Scholar
  110. 110.
    Mohmmad Abdul H, Butterfield DA (2005) Protection against amyloid beta-peptide (1–42)-induced loss of phospholipid asymmetry in synaptosomal membranes by tricyclodecan-9-xanthogenate (D609) and ferulic acid ethyl ester: implications for Alzheimer’s disease. Biochim Biophys Acta 1741:140–148PubMedGoogle Scholar
  111. 111.
    Mohmmad Abdul H, Sultana R, Keller JN, St Clair DK, Markesbery WR, Butterfield DA (2006) Mutations in amyloid precursor protein and presenilin-1 genes increase the basal oxidative stress in murine neuronal cells and lead to increased sensitivity to oxidative stress mediated by amyloid beta-peptide (1–42), HO and kainic acid: implications for Alzheimer’s disease. J Neurochem 96:1322–1335. doi: 10.1111/j.1471-4159.2005.03647.x PubMedGoogle Scholar
  112. 112.
    Mohmmad Abdul H, Wenk GL, Gramling M, Hauss-Wegrzyniak B, Butterfield DA (2004) APP and PS-1 mutations induce brain oxidative stress independent of dietary cholesterol: implications for Alzheimer’s disease. Neurosci Lett 368:148–150. doi: 10.1016/j.neulet.2004.06.077 PubMedGoogle Scholar
  113. 113.
    Montine TJ, Neely MD, Quinn JF, Beal MF, Markesbery WR, Roberts LJ, Morrow JD (2002) Lipid peroxidation in aging brain and Alzheimer’s disease. Free Radic Biol Med 33:620–626. doi: 10.1016/S0891-5849(02)00807-9 PubMedGoogle Scholar
  114. 114.
    Morris JC (2005) Mild cognitive impairment and preclinical Alzheimer’s disease. Geriatrics Suppl:9–14Google Scholar
  115. 115.
    Munch G, Thome J, Foley P, Schinzel R, Riederer P (1997) Advanced glycation endproducts in ageing and Alzheimer’s disease. Brain Res Brain Res Rev 23:134–143. doi: 10.1016/S0165-0173(96)00016-1 PubMedGoogle Scholar
  116. 116.
    Murphy MP, Beckett TL, Ding Q, Patel E, Markesbery WR, St Clair DK, LeVine H 3rd, Keller JN (2007) Abeta solubility and deposition during AD progression and in APPxPS-1 knock-in mice. Neurobiol Dis 27:301–311. doi: 10.1016/j.nbd.2007.06.002 PubMedGoogle Scholar
  117. 117.
    Murray IV, Sindoni ME, Axelsen PH (2005) Promotion of oxidative lipid membrane damage by amyloid beta proteins. Biochemistry 44:12606–12613. doi: 10.1021/bi050926p PubMedGoogle Scholar
  118. 118.
    Negash S, Petersen LE, Geda YE, Knopman DS, Boeve BF, Smith GE, Ivnik RJ, Howard DV, Howard JH Jr, Petersen RC (2007) Effects of ApoE genotype and mild cognitive impairment on implicit learning. Neurobiol Aging 28:885–893. doi: 10.1016/j.neurobiolaging.2006.04.004 PubMedGoogle Scholar
  119. 119.
    Oda T, Wals P, Osterburg HH, Johnson SA, Pasinetti GM, Morgan TE, Rozovsky I, Stine WB, Snyder SW, Holzman TF et al (1995) Clusterin (apoJ) alters the aggregation of amyloid beta-peptide (A beta 1–42) and forms slowly sedimenting Abeta complexes that cause oxidative stress. Exp Neurol 136:22–31. doi: 10.1006/exnr.1995.1080 PubMedGoogle Scholar
  120. 120.
    Ojika K (1998). Hippocampal cholinergic neurostimulating peptide Seikagaku 70:1175–1180Google Scholar
  121. 121.
    Opii WO, Joshi G, Head E, Milgram NW, Muggenburg BA, Klein JB, Pierce WM, Cotman CW, Butterfield DA (2008) Proteomic identification of brain proteins in the canine model of human aging following a long-term treatment with antioxidants and a program of behavioral enrichment: relevance to Alzheimer’s disease. Neurobiol Aging 29:51–70. doi: 10.1016/j.neurobiolaging.2006.09.012 PubMedGoogle Scholar
  122. 122.
    Pancholi V (2001) Multifunctional alpha-enolase: its role in diseases. Cell Mol Life Sci 58:902–920. doi: 10.1007/PL00000910 PubMedGoogle Scholar
  123. 123.
    Parnetti L, Palumbo B, Cardinali L, Loreti F, Chionne F, Cecchetti R, Senin U (1995) Cerebrospinal fluid neuron-specific enolase in Alzheimer’s disease and vascular dementia. Neurosci Lett 183:43–45. doi: 10.1016/0304-3940(94)11110-5 PubMedGoogle Scholar
  124. 124.
    Pastorino L, Sun A, Lu PJ, Zhou XZ, Balastik M, Finn G, Wulf G, Lim J, Li SH, Li X, Xia W, Nicholson LK, Lu KP (2006) The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production. Nature 440:528–534. doi: 10.1038/nature04543 PubMedGoogle Scholar
  125. 125.
    Perluigi M, Fai Poon H, Hensley K, Pierce WM, Klein JB, Calabrese V, De Marco C, Butterfield DA (2005) Proteomic analysis of 4-hydroxy-2-nonenal-modified proteins in G93A-SOD1 transgenic mice—a model of familial amyotrophic lateral sclerosis. Free Radic Biol Med 38:960–968. doi: 10.1016/j.freeradbiomed.2004.12.021 PubMedGoogle Scholar
  126. 126.
    Perluigi M, Joshi G, Sultana R, Calabrese V, De Marco C, Coccia R, Butterfield DA (2006) In vivo protection by the xanthate tricyclodecan-9-yl-xanthogenate against amyloid beta-peptide (1–42)-induced oxidative stress. Neuroscience 138:1161–1170. doi: 10.1016/j.neuroscience.2005.12.004 PubMedGoogle Scholar
  127. 127.
    Perluigi M, Joshi G, Sultana R, Calabrese V, De Marco C, Coccia R, Cini C, Butterfield DA (2006) In vivo protective effects of ferulic acid ethyl ester against amyloid-beta peptide 1–42-induced oxidative stress. J Neurosci Res 84:418–426. doi: 10.1002/jnr.20879 PubMedGoogle Scholar
  128. 128.
    Perluigi M, Sultana R, Cenini G, Di Domenico F, Memo M, Pierce WM, Coccia R, Butterfield DA (2009) Redox proteomics identification of HNE-modified brain proteins in Alzheimers disease: Role of lipid peroxidation in AD pathogenesis. Proteomics Clin Appli (Accepted)Google Scholar
  129. 129.
    Perry EK, Curtis M, Dick DJ, Candy JM, Atack JR, Bloxham CA, Blessed G, Fairbairn A, Tomlinson BE, Perry RH (1985) Cholinergic correlates of cognitive impairment in Parkinson’s disease: comparisons with Alzheimer’s disease. J Neurol Neurosurg Psychiatry 48:413–421. doi: 10.1136/jnnp.48.5.413 PubMedGoogle Scholar
  130. 130.
    Pestova TV, Hellen CU (2000) The structure and function of initiation factors in eukaryotic protein synthesis. Cell Mol Life Sci 57:651–674. doi: 10.1007/PL00000726 PubMedGoogle Scholar
  131. 131.
    Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E (1999) Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 56:303–308. doi: 10.1001/archneur.56.3.303 PubMedGoogle Scholar
  132. 132.
    Poon HF, Farr SA, Thongboonkerd V, Lynn BC, Banks WA, Morley JE, Klein JB, Butterfield DA (2005) Proteomic analysis of specific brain proteins in aged SAMP8 mice treated with alpha-lipoic acid: implications for aging and age-related neurodegenerative disorders. Neurochem Int 46:159–168. doi: 10.1016/j.neuint.2004.07.008 PubMedGoogle Scholar
  133. 133.
    Poon HF, Shepherd HM, Reed TT, Calabrese V, Stella AM, Pennisi G, Cai J, Pierce WM, Klein JB, Butterfield DA (2006) Proteomics analysis provides insight into caloric restriction mediated oxidation and expression of brain proteins associated with age-related impaired cellular processes: Mitochondrial dysfunction, glutamate dysregulation and impaired protein synthesis. Neurobiol Aging 27:1020–1034. doi: 10.1016/j.neurobiolaging.2005.05.014 PubMedGoogle Scholar
  134. 134.
    Power JH, Asad S, Chataway TK, Chegini F, Manavis J, Temlett JA, Jensen PH, Blumbergs PC, Gai WP (2008) Peroxiredoxin 6 in human brain: molecular forms, cellular distribution and association with Alzheimer’s disease pathology. Acta Neuropathol 115:611–622. doi: 10.1007/s00401-008-0373-3 PubMedGoogle Scholar
  135. 135.
    Ralat LA, Manevich Y, Fisher AB, Colman RF (2006) Direct evidence for the formation of a complex between 1-cysteine peroxiredoxin and glutathione S-transferase pi with activity changes in both enzymes. Biochemistry 45:360–372. doi: 10.1021/bi0520737 PubMedGoogle Scholar
  136. 136.
    Ramakers IH, Visser PJ, Aalten P, Bekers O, Sleegers K, van Broeckhoven CL, Jolles J, Verhey FR (2008) The association between APOE genotype and memory dysfunction in subjects with mild cognitive impairment is related to age and Alzheimer pathology. Dement Geriatr Cogn Disord 26:101–108. doi: 10.1159/000144072 PubMedGoogle Scholar
  137. 137.
    Ramakrishnan P, Dickson DW, Davies P (2003) Pin1 colocalization with phosphorylated tau in Alzheimer’s disease and other tauopathies. Neurobiol Dis 14:251–264. doi: 10.1016/S0969-9961(03)00109-8 PubMedGoogle Scholar
  138. 138.
    Reed T, Perluigi M, Sultana R, Pierce WM, Klein JB, Turner DM, Coccia R, Markesbery WR, Butterfield DA (2008) Redox proteomic identification of 4-hydroxy-2-nonenal-modified brain proteins in amnestic mild cognitive impairment: insight into the role of lipid peroxidation in the progression and pathogenesis of Alzheimer’s disease. Neurobiol Dis 30:107–120. doi: 10.1016/j.nbd.2007.12.007 PubMedGoogle Scholar
  139. 139.
    Renes J, de Vries EE, Hooiveld GJ, Krikken I, Jansen PL, Muller M (2000) Multidrug resistance protein MRP1 protects against the toxicity of the major lipid peroxidation product 4-hydroxynonenal. Biochem J 350(Pt 2):555–561. doi: 10.1042/0264-6021:3500555 PubMedGoogle Scholar
  140. 140.
    Rinaldi P, Polidori MC, Metastasio A, Mariani E, Mattioli P, Cherubini A, Catani M, Cecchetti R, Senin U, Mecocci P (2003) Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer’s disease. Neurobiol Aging 24:915–919. doi: 10.1016/S0197-4580(03)00031-9 PubMedGoogle Scholar
  141. 141.
    Sadik G, Tanaka T, Kato K, Yamamori H, Nessa BN, Morihara T, Takeda M (2008) Phosphorylation of tau at Ser214 mediates its interaction with 14-3-3 protein: implications for the mechanism of tau aggregation. J Neurochem 108:33–43PubMedGoogle Scholar
  142. 142.
    Santoni V, Molloy M, Rabilloud T (2000) Membrane proteins and proteomics: un amour impossible? Electrophoresis 21:1054–1070. doi: 10.1002/(SICI)1522-2683(20000401)21:6<1054::AID-ELPS1054>3.0.CO;2-8 PubMedGoogle Scholar
  143. 143.
    Santpere G, Puig B, Ferrer I (2007) Oxidative damage of 14-3-3 zeta and gamma isoforms in Alzheimer’s disease and cerebral amyloid angiopathy. Neuroscience 146:1640–1651. doi: 10.1016/j.neuroscience.2007.03.013 PubMedGoogle Scholar
  144. 144.
    Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81:741–766PubMedGoogle Scholar
  145. 145.
    Shimizu H, Banno Y, Sumi N, Naganawa T, Kitajima Y, Nozawa Y (1999) Activation of p38 mitogen-activated protein kinase and caspases in UVB-induced apoptosis of human keratinocyte HaCaT cells. J Invest Dermatol 112:769–774. doi: 10.1046/j.1523-1747.1999.00582.x PubMedGoogle Scholar
  146. 146.
    Sly WS, Hu PY (1995) Human carbonic anhydrases and carbonic anhydrase deficiencies. Annu Rev Biochem 64:375–401. doi: 10.1146/ PubMedGoogle Scholar
  147. 147.
    Smith MA, Richey Harris PL, Sayre LM, Beckman JS, Perry G (1997) Widespread peroxynitrite-mediated damage in Alzheimer’s disease. J Neurosci 17:2653–2657PubMedGoogle Scholar
  148. 148.
    Smith MA, Richey PL, Taneda S, Kutty RK, Sayre LM, Monnier VM, Perry G (1994) Advanced Maillard reaction end products, free radicals, and protein oxidation in Alzheimer’s disease. Ann N Y Acad Sci 738:447–454PubMedGoogle Scholar
  149. 149.
    Spires TL, Meyer-Luehmann M, Stern EA, McLean PJ, Skoch J, Nguyen PT, Bacskai BJ, Hyman BT (2005) Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy. J Neurosci 25:7278–7287. doi: 10.1523/JNEUROSCI.1879-05.2005 PubMedGoogle Scholar
  150. 150.
    Stadtman ER, Berlett BS (1997) Reactive oxygen-mediated protein oxidation in aging and disease. Chem Res Toxicol 10:485–494. doi: 10.1021/tx960133r PubMedGoogle Scholar
  151. 151.
    Stenbeck G (1998) Soluble NSF-attachment proteins. Int J Biochem Cell Biol 30:573–577. doi: 10.1016/S1357-2725(97)00064-2 PubMedGoogle Scholar
  152. 152.
    Subramaniam R, Roediger F, Jordan B, Mattson MP, Keller JN, Waeg G, Butterfield DA (1997) The lipid peroxidation product, 4-hydroxy-2-trans-nonenal, alters the conformation of cortical synaptosomal membrane proteins. J Neurochem 69:1161–1169PubMedCrossRefGoogle Scholar
  153. 153.
    Suh YH, Checler F (2002) Amyloid precursor protein, presenilins, and alpha-synuclein: molecular pathogenesis and pharmacological applications in Alzheimer’s disease. Pharmacol Rev 54:469–525. doi: 10.1124/pr.54.3.469 PubMedGoogle Scholar
  154. 154.
    Sultana R, Boyd-Kimball D, Poon HF, Cai J, Pierce WM, Klein JB, Markesbery WR, Zhou XZ, Lu KP, Butterfield DA (2006) Oxidative modification and down-regulation of Pin1 in Alzheimer’s disease hippocampus: a redox proteomics analysis. Neurobiol Aging 27:918–925. doi: 10.1016/j.neurobiolaging.2005.05.005 PubMedGoogle Scholar
  155. 155.
    Sultana R, Boyd-Kimball D, Poon HF, Cai J, Pierce WM, Klein JB, Merchant M, Markesbery WR, Butterfield DA (2006) Redox proteomics identification of oxidized proteins in Alzheimer’s disease hippocampus and cerebellum: an approach to understand pathological and biochemical alterations in AD. Neurobiol Aging 27:1564–1576. doi: 10.1016/j.neurobiolaging.2005.09.021 PubMedGoogle Scholar
  156. 156.
    Sultana R, Butterfield DA (2004) Oxidatively modified GST and MRP1 in Alzheimer’s disease brain: implications for accumulation of reactive lipid peroxidation products. Neurochem Res 29:2215–2220. doi: 10.1007/s11064-004-7028-0 PubMedGoogle Scholar
  157. 157.
    Sultana R, Newman S, Mohmmad-Abdul H, Keller JN, Butterfield DA (2004) Protective effect of the xanthate, D609, on Alzheimer’s amyloid beta-peptide (1–42)-induced oxidative stress in primary neuronal cells. Free Radic Res 38:449–458. doi: 10.1080/1071576042000206478 PubMedGoogle Scholar
  158. 158.
    Sultana R, Newman SF, Abdul HM, Cai J, Pierce WM, Klein JB, Merchant M, Butterfield DA (2006) Protective effect of D609 against amyloid-beta1–42-induced oxidative modification of neuronal proteins: redox proteomics study. J Neurosci Res 84:409–417. doi: 10.1002/jnr.20876 PubMedGoogle Scholar
  159. 159.
    Sultana R, Perluigi M, Butterfield DA (2006) Redox proteomics identification of oxidatively modified proteins in Alzheimer’s disease brain and in vivo and in vitro models of AD centered around Abeta(1–42). J Chromatogr B Analyt Technol Biomed Life Sci 833:3–11. doi: 10.1016/j.jchromb.2005.09.024 PubMedGoogle Scholar
  160. 160.
    Sultana R, Piroddi M, Galli F, Butterfield DA (2008) Protein levels and activity of some antioxidant enzymes in hippocampus of subjects with amnestic mild cognitive impairment. Neurochem Res 33:2540–2546. doi: 10.1007/s11064-008-9593-0 PubMedGoogle Scholar
  161. 161.
    Sultana R, Poon HF, Cai J, Pierce WM, Merchant M, Klein JB, Markesbery WR, Butterfield DA (2006) Identification of nitrated proteins in Alzheimer’s disease brain using a redox proteomics approach. Neurobiol Dis 22:76–87. doi: 10.1016/j.nbd.2005.10.004 PubMedGoogle Scholar
  162. 162.
    Sultana R, Ravagna A, Mohmmad-Abdul H, Calabrese V, Butterfield DA (2005) Ferulic acid ethyl ester protects neurons against amyloid beta- peptide(1–42)-induced oxidative stress and neurotoxicity: relationship to antioxidant activity. J Neurochem 92:749–758. doi: 10.1111/j.1471-4159.2004.02899.x PubMedGoogle Scholar
  163. 163.
    Sultana R, Reed T, Perluigi M, Coccia R, Pierce WM, Butterfield DA (2007) Proteomic identification of nitrated brain proteins in amnestic mild cognitive impairment: a regional study. J Cell Mol Med 11:839–851. doi: 10.1111/j.1582-4934.2007.00065.x PubMedGoogle Scholar
  164. 164.
    Tamagno E, Parola M, Guglielmotto M, Santoro G, Bardini P, Marra L, Tabaton M, Danni O (2003) Multiple signaling events in amyloid beta-induced, oxidative stress-dependent neuronal apoptosis. Free Radic Biol Med 35:45–58. doi: 10.1016/S0891-5849(03)00244-2 PubMedGoogle Scholar
  165. 165.
    Tamagno E, Robino G, Obbili A, Bardini P, Aragno M, Parola M, Danni O (2003) H2O2 and 4-hydroxynonenal mediate amyloid beta-induced neuronal apoptosis by activating JNKs and p38MAPK. Exp Neurol 180:144–155. doi: 10.1016/S0014-4886(02)00059-6 PubMedGoogle Scholar
  166. 166.
    Tchaikovskaya T, Fraifeld V, Urphanishvili T, Andorfer JH, Davies P, Listowsky I (2005) Glutathione S-transferase hGSTM3 and ageing-associated neurodegeneration: relationship to Alzheimer’s disease. Mech Ageing Dev 126:309–315. doi: 10.1016/j.mad.2004.08.029 PubMedGoogle Scholar
  167. 167.
    Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580. doi: 10.1002/ana.410300410 PubMedGoogle Scholar
  168. 168.
    Thompson J, Dahlberg AE (2004) Testing the conservation of the translational machinery over evolution in diverse environments: assaying Thermus thermophilus ribosomes and initiation factors in a coupled transcription-translation system from Escherichia coli. Nucleic Acids Res 32:5954–5961. doi: 10.1093/nar/gkh925 PubMedGoogle Scholar
  169. 169.
    Tremblay C, Pilote M, Phivilay A, Emond V, Bennett DA, Calon F (2007) Biochemical characterization of Abeta and tau pathologies in mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis 12:377–390PubMedGoogle Scholar
  170. 170.
    Uchida K, Stadtman ER (1992) Modification of histidine residues in proteins by reaction with 4-hydroxynonenal. Proc Natl Acad Sci USA 89:4544–4548. doi: 10.1073/pnas.89.10.4544 PubMedGoogle Scholar
  171. 171.
    Viola KL, Velasco PT, Klein WL (2008) Why Alzheimer’s is a disease of memory: the attack on synapses by A beta oligomers (ADDLs). J Nutr Health Aging 12:51S–57S. doi: 10.1007/BF02982587 PubMedGoogle Scholar
  172. 172.
    Walsh DM, Hartley DM, Kusumoto Y, Fezoui Y, Condron MM, Lomakin A, Benedek GB, Selkoe DJ, Teplow DB (1999) Amyloid beta-protein fibrillogenesis. Structure and biological activity of protofibrillar intermediates. J Biol Chem 274:25945–25952. doi: 10.1074/jbc.274.36.25945 PubMedGoogle Scholar
  173. 173.
    Walsh DM, Klyubin I, Fadeeva JV, Rowan MJ, Selkoe DJ (2002) Amyloid-beta oligomers: their production, toxicity and therapeutic inhibition. Biochem Soc Trans 30:552–557. doi: 10.1042/BST0300552 PubMedGoogle Scholar
  174. 174.
    Watson GS, Craft S (2004) Modulation of memory by insulin and glucose: neuropsychological observations in Alzheimer’s disease. Eur J Pharmacol 490:97–113. doi: 10.1016/j.ejphar.2004.02.048 PubMedGoogle Scholar
  175. 175.
    Wevers A, Witter B, Moser N, Burghaus L, Banerjee C, Steinlein OK, Schutz U, de Vos RA, Steur EN, Lindstrom J, Schroder H (2000) Classical Alzheimer features and cholinergic dysfunction: towards a unifying hypothesis? Acta Neurol Scand Suppl 176:42–48. doi: 10.1034/j.1600-0404.2000.00306.x PubMedGoogle Scholar
  176. 176.
    Whitehouse PJ, Price DL, Clark AW, Coyle JT, DeLong MR (1981) Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann Neurol 10:122–126. doi: 10.1002/ana.410100203 PubMedGoogle Scholar
  177. 177.
    Williams TI, Lynn BC, Markesbery WR, Lovell MA (2006) Increased levels of 4-hydroxynonenal and acrolein, neurotoxic markers of lipid peroxidation, in the brain in Mild Cognitive Impairment and early Alzheimer’s disease. Neurobiol Aging 27:1094–1099. doi: 10.1016/j.neurobiolaging.2005.06.004 PubMedGoogle Scholar
  178. 178.
    Yatin SM, Varadarajan S, Butterfield DA (2000) Vitamin E prevents Alzheimer’s amyloid beta-peptide (1–42)-induced neuronal protein oxidation and reactive oxygen species production. J Alzheimers Dis 2:123–131PubMedGoogle Scholar
  179. 179.
    Yatin SM, Varadarajan S, Link CD, Butterfield DA (1999) In vitro and in vivo oxidative stress associated with Alzheimer’s amyloid beta-peptide (1–42). Neurobiol Aging 20:325–330. doi: 10.1016/S0197-4580(99)00056-1 discussion 39-42PubMedGoogle Scholar
  180. 180.
    Zarkovic K (2003) 4-hydroxynonenal and neurodegenerative diseases. Mol Aspects Med 24:293–303. doi: 10.1016/S0098-2997(03)00024-4 PubMedGoogle Scholar
  181. 181.
    Zhou XZ, Kops O, Werner A, Lu PJ, Shen M, Stoller G, Kullertz G, Stark M, Fischer G, Lu KP (2000) Pin1-dependent prolyl isomerization regulates dephosphorylation of Cdc25C and tau proteins. Mol Cell 6:873–883. doi: 10.1016/S1097-2765(05)00083-3 PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Rukhsana Sultana
    • 1
    • 2
  • Marzia Perluigi
    • 3
  • D. Allan Butterfield
    • 1
    • 2
  1. 1.Department of Chemistry, Center of Membrane SciencesUniversity of KentuckyLexingtonUSA
  2. 2.Sanders-Brown Center on AgingUniversity of KentuckyLexingtonUSA
  3. 3.Department of Biochemical SciencesUniversity of Rome “La Sapienza”RomeItaly

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