Neuroscience Bulletin

, Volume 30, Issue 2, pp 271–281 | Cite as

Oxidative stress in Alzheimer’s disease

  • Zhichun Chen
  • Chunjiu ZhongEmail author


Oxidative stress plays a significant role in the pathogenesis of Alzheimer’s disease (AD), a devastating disease of the elderly. The brain is more vulnerable than other organs to oxidative stress, and most of the components of neurons (lipids, proteins, and nucleic acids) can be oxidized in AD due to mitochondrial dysfunction, increased metal levels, inflammation, and β-amyloid (Aβ) peptides. Oxidative stress participates in the development of AD by promoting Aβ deposition, tau hyperphosphorylation, and the subsequent loss of synapses and neurons. The relationship between oxidative stress and AD suggests that oxidative stress is an essential part of the pathological process, and antioxidants may be useful for AD treatment.


Alzheimer’s disease oxidative stress β-amyloid tau metals antioxidants 


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  1. [1]
    Sokoloff L. Energetics of functional activation in neural tissues. Neurochem Res 1999, 24: 321–329.PubMedGoogle Scholar
  2. [2]
    Tholey G, Ledig M. Neuronal and astrocytic plasticity: metabolic aspects. Ann Med Interne (Paris) 1990, 141Suppl 1: 13–18.Google Scholar
  3. [3]
    Pratico D. Oxidative stress hypothesis in Alzheimer’s disease: a reappraisal. Trends Pharmacol Sci 2008, 29: 609–615.PubMedGoogle Scholar
  4. [4]
    Nunomura A, Castellani RJ, Zhu X, Moreira PI, Perry G, Smith MA. Involvement of oxidative stress in Alzheimer disease. J Neuropathol Exp Neurol 2006, 65: 631–641.PubMedGoogle Scholar
  5. [5]
    Pocernich C, Butterfield D. Elevation of glutathione as a therapeutic strategy in Alzheimer disease. Biochim Biophys Acta 2012, 1822(5): 625–630.PubMedCentralPubMedGoogle Scholar
  6. [6]
    Behl C, Moosmann B. Antioxidant neuroprotection in Alzheimer’s disease as preventive and therapeutic approach. Free Radic Biol Med 2002, 15;33(2):182–191.PubMedGoogle Scholar
  7. [7]
    Moosmann B, Behl C. Antioxidants as treatment for neurodegenerative disorders. Expert Opin Investig Drugs 2002, 11(10): 1407–1435.PubMedGoogle Scholar
  8. [8]
    Torres LL, Quaglio NB, de Souza GT, Garcia RT, Dati LM, Moreira WL, et al. Peripheral oxidative stress biomarkers in mild cognitive impairment and Alzheimer’s disease. J Alzheimers Dis 2011, 26: 59–68.PubMedGoogle Scholar
  9. [9]
    Beal MF. Oxidative damage as an early marker of Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging 2005, 26: 585–586.PubMedGoogle Scholar
  10. [10]
    Beal M. Oxidatively modiied proteins in aging and disease. Free Radic Biol Med 2002, 32(9): 797–803.PubMedGoogle Scholar
  11. [11]
    Butterfield D, Kanski J. Brain protein oxidation in agerelated neurodegenerative disorders that are associated with aggregated proteins. Mech Ageing Dev 2001, 122(9): 945–962.PubMedGoogle Scholar
  12. [12]
    Zhao Y, Zhao B. Oxidative stress and the pathogenesis of Alzheimer’s disease. Oxid Med Cell Longev 2013, 2013: 316523.PubMedCentralPubMedGoogle Scholar
  13. [13]
    Lovell MA, Ehmann WD, Butler SM, Markesbery WR. Elevated thiobarbituric acid-reactive substances and antioxidant enzyme activity in the brain in Alzheimer’s disease. Neurology 1995, 45: 1594–1601.PubMedGoogle Scholar
  14. [14]
    Marcus DL, Thomas C, Rodriguez C, Simberkoff K, Tsai JS, Strafaci JA, et al. Increased peroxidation and reduced antioxidant enzyme activity in Alzheimer’s disease. Exp Neurol 1998, 150: 40–44.PubMedGoogle Scholar
  15. [15]
    Pratico D, Clark CM, Lee VM, Trojanowski JQ, Rokach J, FitzGerald GA. Increased 8,12-iso-iPF2alpha-VI in Alzheimer’s disease: correlation of a noninvasive index of lipid peroxidation with disease severity. Ann Neurol 2000, 48: 809–812.PubMedGoogle Scholar
  16. [16]
    Williams TI, Lynn BC, Markesbery WR, Lovell MA. 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 2006, 27: 1094–1099.PubMedGoogle Scholar
  17. [17]
    Omar RA, Chyan YJ, Andorn AC, Poeggeler B, Robakis NK, Pappolla MA. Increased expression but reduced activity of antioxidant enzymes in Alzheimer’s disease. J Alzheimers Dis 1999, 1: 139–145.PubMedGoogle Scholar
  18. [18]
    Federico A, Cardaioli E, Da Pozzo P, Formichi P, Gallus GN, Radi E. Mitochondria, oxidative stress and neurodegeneration. J Neurol Sci 2012, 322: 254–262.PubMedGoogle Scholar
  19. [19]
    Yan MH, Wang X, Zhu X. Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease. Free Radic Biol Med 2013, 62: 90–101.PubMedCentralPubMedGoogle Scholar
  20. [20]
    Ayton S, Lei P, Bush AI. Metallostasis in Alzheimer’s disease. Free Radic Biol Med 2013, 62: 76–89.PubMedGoogle Scholar
  21. [21]
    Greenough MA, Camakaris J, Bush AI. Metal dyshomeostasis and oxidative stress in Alzheimer’s disease. Neurochem Int 2013, 62: 540–555.PubMedGoogle Scholar
  22. [22]
    Dias-Santagata D, Fulga TA, Duttaroy A, Feany MB. Oxidative stress mediates tau-induced neurodegeneration in Drosophila. J Clin Invest 2007, 117: 236–245.PubMedCentralPubMedGoogle Scholar
  23. [23]
    Stamer K, Vogel R, Thies E, Mandelkow E, Mandelkow EM. Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress. J Cell Biol 2002, 156: 1051–1063.PubMedCentralPubMedGoogle Scholar
  24. [24]
    Candore G, Bulati M, Caruso C, Castiglia L, Colonna-Romano G, Di Bona D, et al. Inflammation, cytokines, immune response, apolipoprotein E, cholesterol, and oxidative stress in Alzheimer disease: therapeutic implications. Rejuvenation Res 2010, 13: 301–313.PubMedGoogle Scholar
  25. [25]
    Lee YJ, Han SB, Nam SY, Oh KW, Hong JT. Inflammation and Alzheimer’s disease. Arch Pharm Res 2010, 33: 1539–1556.PubMedGoogle Scholar
  26. [26]
    Ansari MA, Scheff SW. Oxidative stress in the progression of Alzheimer disease in the frontal cortex. J Neuropathol Exp Neurol 2010, 69: 155–167.PubMedCentralPubMedGoogle Scholar
  27. [27]
    Manczak M, Mao P, Calkins MJ, Cornea A, Reddy AP, Murphy MP, et al. Mitochondria-targeted antioxidants protect against amyloid-beta toxicity in Alzheimer’s disease neurons. J Alzheimers Dis 2010, 20Suppl 2: S609–631.PubMedCentralPubMedGoogle Scholar
  28. [28]
    Mattson MP. Pathways towards and away from Alzheimer’s disease. Nature 2004, 430: 631–639.PubMedCentralPubMedGoogle Scholar
  29. [29]
    Reddy PH. Mitochondrial oxidative damage in aging and Alzheimer’s disease: implications for mitochondrially targeted antioxidant therapeutics. J Biomed Biotechnol 2006, 2006: 31372.PubMedCentralPubMedGoogle Scholar
  30. [30]
    Skoumalova A, Hort J. Blood markers of oxidative stress in Alzheimer’s disease. J Cell Mol Med 2012, 16: 2291–2300.PubMedGoogle Scholar
  31. [31]
    Soderberg M, Edlund C, Kristensson K, Dallner G. Fatty acid composition of brain phospholipids in aging and in Alzheimer’s disease. Lipids 1991, 26: 421–425.PubMedGoogle Scholar
  32. [32]
    Butterfield DA, Reed T, Perluigi M, De Marco C, Coccia R, Cini C, et al. Elevated protein-bound levels of the lipid peroxidation product, 4-hydroxy-2-nonenal, in brain from persons with mild cognitive impairment. Neurosci Lett 2006, 397: 170–173.PubMedGoogle Scholar
  33. [33]
    Keller JN, Schmitt FA, Scheff SW, Ding Q, Chen Q, Butterfield DA, et al. Evidence of increased oxidative damage in subjects with mild cognitive impairment. Neurology 2005, 64: 1152–1156.PubMedGoogle Scholar
  34. [34]
    Roberts LJ, 2nd, Montine TJ, Markesbery WR, Tapper AR, Hardy P, Chemtob S, et al. Formation of isoprostane-like compounds (neuroprostanes) in vivo from docosahexaenoic acid. J Biol Chem 1998, 273: 13605–13612.PubMedGoogle Scholar
  35. [35]
    Montine TJ, Markesbery WR, Morrow JD, Roberts LJ, 2nd. Cerebrospinal fluid F2-isoprostane levels are increased in Alzheimer’s disease. Ann Neurol 1998, 44: 410–413.PubMedGoogle Scholar
  36. [36]
    Singh M, Dang TN, Arseneault M, Ramassamy C. Role of by-products of lipid oxidation in Alzheimer’s disease brain: a focus on acrolein. J Alzheimers Dis 2010, 21: 741–756.PubMedGoogle Scholar
  37. [37]
    Ahmed N, Ahmed U, Thornalley PJ, Hager K, Fleischer G, Munch G. Protein glycation, oxidation and nitration adduct residues and free adducts of cerebrospinal fluid in Alzheimer’s disease and link to cognitive impairment. J Neurochem 2005, 92: 255–263.PubMedGoogle Scholar
  38. [38]
    Butterfield DA, Reed TT, Perluigi M, De Marco C, Coccia R, Keller JN, et al. Elevated levels of 3-nitrotyrosine in brain from subjects with amnestic mild cognitive impairment: implications for the role of nitration in the progression of Alzheimer’s disease. Brain Res 2007, 1148: 243–248.PubMedCentralPubMedGoogle Scholar
  39. [39]
    Mecocci P, MacGarvey U, Beal MF. Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease. Ann Neurol 1994, 36: 747–751.PubMedGoogle Scholar
  40. [40]
    Nunomura A, Perry G, Pappolla MA, Wade R, Hirai K, Chiba S, et al. RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer’s disease. J Neurosci 1999, 19: 1959–1964.PubMedGoogle Scholar
  41. [41]
    Mullaart E, Boerrigter ME, Ravid R, Swaab DF, Vijg J. Increased levels of DNA breaks in cerebral cortex of Alzheimer’s disease patients. Neurobiol Aging 1990, 11: 169–173.PubMedGoogle Scholar
  42. [42]
    Grivennikova VG, Vinogradov AD. Generation of superoxide by the mitochondrial Complex I. Biochim Biophys Acta 2006, 1757: 553–561.PubMedGoogle Scholar
  43. [43]
    Tan S, Sagara Y, Liu Y, Maher P, Schubert D. The regulation of reactive oxygen species production during programmed cell death. J Cell Biol 1998, 141: 1423–1432.PubMedCentralPubMedGoogle Scholar
  44. [44]
    Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, et al. Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci 2001, 21: 3017–3023.PubMedGoogle Scholar
  45. [45]
    Silva DF, Selfridge JE, Lu J, E L, Cardoso SM, Swerdlow RH. Mitochondrial abnormalities in Alzheimer’s disease: possible targets for therapeutic intervention. Adv Pharmacol 2012, 64: 83–126.PubMedCentralPubMedGoogle Scholar
  46. [46]
    Mutisya EM, Bowling AC, Beal MF. Cortical cytochrome oxidase activity is reduced in Alzheimer’s disease. J Neurochem 1994, 63: 2179–2184.PubMedGoogle Scholar
  47. [47]
    Anantharaman M, Tangpong J, Keller JN, Murphy MP, Markesbery WR, Kiningham KK, et al. 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 2006, 168: 1608–1618.PubMedCentralPubMedGoogle Scholar
  48. [48]
    Casley CS, Canevari L, Land JM, Clark JB, Sharpe MA. Beta-amyloid inhibits integrated mitochondrial respiration and key enzyme activities. J Neurochem 2002, 80: 91–100.PubMedGoogle Scholar
  49. [49]
    Wang X, Su B, Siedlak SL, Moreira PI, Fujioka H, Wang Y, et al. Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proc Natl Acad Sci U S A 2008, 105: 19318–19323.PubMedCentralPubMedGoogle Scholar
  50. [50]
    Crouch PJ, Harding SM, White AR, Camakaris J, Bush AI, Masters CL. Mechanisms of A beta mediated neurodegeneration in Alzheimer’s disease. Int J Biochem Cell Biol 2008, 40: 181–198.PubMedGoogle Scholar
  51. [51]
    Manczak M, Anekonda TS, Henson E, Park BS, Quinn J, Reddy PH. Mitochondria are a direct site of Aβ accumulation in Alzheimer’s disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet 2006, 15: 1437–1449.PubMedGoogle Scholar
  52. [52]
    Rodrigues CM, Sola S, Brito MA, Brondino CD, Brites D, Moura JJ. Amyloid beta-peptide disrupts mitochondrial membrane lipid and protein structure: protective role of tauroursodeoxycholate. Biochem Biophys Res Commun 2001, 281: 468–474.PubMedGoogle Scholar
  53. [53]
    Apelt J, Bigl M, Wunderlich P, Schliebs R. Aging-related increase in oxidative stress correlates with developmental pattern of beta-secretase activity and beta-amyloid plaque formation in transgenic Tg2576 mice with Alzheimer-like pathology. Int J Dev Neurosci 2004, 22: 475–484.PubMedGoogle Scholar
  54. [54]
    Manczak M, Anekonda TS, Henson E, Park BS, Quinn J, Reddy PH. Mitochondria are a direct site of A beta accumulation in Alzheimer’s disease neurons: implications for free radical generation and oxidative damage in disease progression. Hum Mol Genet 2006, 15: 1437–1449.PubMedGoogle Scholar
  55. [55]
    Matsuoka Y, Picciano M, La Francois J, Duff K. Fibrillar betaamyloid evokes oxidative damage in a transgenic mouse model of Alzheimer’s disease. Neuroscience 2001, 104: 609–613.PubMedGoogle Scholar
  56. [56]
    Takuma K, Yao J, Huang J, Xu H, Chen X, Luddy J, et al. ABAD enhances Abeta-induced cell stress via mitochondrial dysfunction. FASEB J 2005, 19: 597–598.PubMedGoogle Scholar
  57. [57]
    Yu T, Robotham JL, Yoon Y. Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc Natl Acad Sci U S A 2006, 103: 2653–2658.PubMedCentralPubMedGoogle Scholar
  58. [58]
    Bonda DJ, Wang X, Perry G, Smith MA, Zhu X. Mitochondrial dynamics in Alzheimer’s disease: opportunities for future treatment strategies. Drugs Aging 2010, 27: 181–192.PubMedCentralPubMedGoogle Scholar
  59. [59]
    Wang X, Su B, Fujioka H, Zhu X. Dynamin-like protein 1 reduction underlies mitochondrial morphology and distribution abnormalities in fibroblasts from sporadic Alzheimer’s disease patients. Am J Pathol 2008, 173: 470–482.PubMedCentralPubMedGoogle Scholar
  60. [60]
    Baldeiras I, Santana I, Proenca MT, Garrucho MH, Pascoal R, Rodrigues A, et al. Oxidative damage and progression to Alzheimer’s disease in patients with mild cognitive impairment. J Alzheimers Dis 2010, 21: 1165–1177.PubMedGoogle Scholar
  61. [61]
    Echtay KS. Mitochondrial uncoupling proteins—what is their physiological role? Free Radic Biol Med 2007, 43: 1351–1371.PubMedGoogle Scholar
  62. [62]
    Wu Z, Zhang J, Zhao B. Superoxide anion regulates the mitochondrial free Ca2+ through uncoupling proteins. Antioxid Redox Signal 2009, 11: 1805–1818.PubMedGoogle Scholar
  63. [63]
    Piccolo G, Banfi P, Azan G, Rizzuto R, Bisson R, Sandona D, et al. Biological markers of oxidative stress in mitochondrial myopathies with progressive external ophthalmoplegia. J Neurol Sci 1991, 105: 57–60.PubMedGoogle Scholar
  64. [64]
    Smits P, Mattijssen S, Morava E, van den Brand M, van den Brandt F, Wijburg F, et al. Functional consequences of mitochondrial tRNA Trp and tRNA Arg mutations causing combined OXPHOS defects. Eur J Hum Genet 2010, 18: 324–329.PubMedCentralPubMedGoogle Scholar
  65. [65]
    Wu SB, Ma YS, Wu YT, Chen YC, Wei YH. Mitochondrial DNA mutation-elicited oxidative stress, oxidative damage, and altered gene expression in cultured cells of patients with MERRF syndrome. Mol Neurobiol 2010, 41: 256–266.PubMedGoogle Scholar
  66. [66]
    Ikawa M, Arakawa K, Hamano T, Nagata M, Nakamoto Y, Kuriyama M, et al. Evaluation of systemic redox states in patients carrying the MELAS A3243G mutation in mitochondrial DNA. Eur Neurol 2012, 67: 232–237.PubMedGoogle Scholar
  67. [67]
    Wong A, Cavelier L, Collins-Schramm HE, Seldin MF, McGrogan M, Savontaus M-L, et al. Differentiation-specific effects of LHON mutations introduced into neuronal NT2 cells. Hum Mol Genet 2002, 11: 431–438.PubMedGoogle Scholar
  68. [68]
    Deibel MA, Ehmann WD, Markesbery WR. Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer’s disease: possible relation to oxidative stress. J Neurol Sci 1996, 143: 137–142.PubMedGoogle Scholar
  69. [69]
    Eskici G, Axelsen PH. Copper and oxidative stress in the pathogenesis of Alzheimer’s disease. Biochemistry 2012, 51: 6289–6311.PubMedGoogle Scholar
  70. [70]
    Jomova K, Vondrakova D, Lawson M, Valko M. Metals, oxidative stress and neurodegenerative disorders. Mol Cell Biochem 2010, 345: 91–104.PubMedGoogle Scholar
  71. [71]
    Curtain CC, Ali F, Volitakis I, Cherny RA, Norton RS, Beyreuther K, et al. Alzheimer’s disease amyloid-beta binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits. J Biol Chem 2001, 276: 20466–20473.PubMedGoogle Scholar
  72. [72]
    Opazo C, Huang X, Cherny RA, Moir RD, Roher AE, White AR, et al. Metalloenzyme-like activity of Alzheimer’s disease beta-amyloid. Cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H2O2. J Biol Chem 2002, 277: 40302–40308.PubMedGoogle Scholar
  73. [73]
    Huang X, Cuajungco MP, Atwood CS, Hartshorn MA, Tyndall JD, Hanson GR, et al. Cu(II) potentiation of alzheimer abeta neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J Biol Chem 1999, 274: 37111–37116.Google Scholar
  74. [74]
    Lynch T, Cherny RA, Bush AI. Oxidative processes in Alzheimer’s disease: the role of abeta-metal interactions. Exp Gerontol 2000, 35: 445–451.PubMedGoogle Scholar
  75. [75]
    Altamura S, Muckenthaler MU. Iron toxicity in diseases of aging: Alzheimer’s disease, Parkinson’s disease and atherosclerosis. J Alzheimers Dis 2009, 16: 879–895.PubMedGoogle Scholar
  76. [76]
    Pulliam JF, Jennings CD, Kryscio RJ, Davis DG, Wilson D, Montine TJ, et al. Association of HFE mutations with neurodegeneration and oxidative stress in Alzheimer’s disease and correlation with APOE. Am J Med Genet B Neuropsychiatr Genet 2003, 119B: 48–53.PubMedGoogle Scholar
  77. [77]
    Honda K, Casadesus G, Petersen RB, Perry G, Smith MA. Oxidative stress and redox-active iron in Alzheimer’s disease. Ann N Y Acad Sci 2004, 1012: 179–182.PubMedGoogle Scholar
  78. [78]
    Wan L, Nie G, Zhang J, Luo Y, Zhang P, Zhang Z, et al. beta-Amyloid peptide increases levels of iron content and oxidative stress in human cell and Caenorhabditis elegans models of Alzheimer disease. Free Radic Biol Med 2011, 50: 122–129.PubMedGoogle Scholar
  79. [79]
    Sensi SL, Rapposelli IG, Frazzini V, Mascetra N. Altered oxidant-mediated intraneuronal zinc mobilization in a triple transgenic mouse model of Alzheimer’s disease. Exp Gerontol 2008, 43: 488–492.PubMedGoogle Scholar
  80. [80]
    Sensi SL, Paoletti P, Bush AI, Sekler I. Zinc in the physiology and pathology of the CNS. Nat Rev Neurosci 2009, 10: 780–791.PubMedGoogle Scholar
  81. [81]
    Goedert M, Spillantini MG. A century of Alzheimer’s disease. Science 2006, 314: 777–781.PubMedGoogle Scholar
  82. [82]
    Petersen RB, Nunomura A, Lee HG, Casadesus G, Perry G, Smith MA, et al. Signal transduction cascades associated with oxidative stress in Alzheimer’s disease. J Alzheimers Dis 2007, 11: 143–152.PubMedGoogle Scholar
  83. [83]
    Cente M, Filipcik P, Pevalova M, Novak M. Expression of a truncated tau protein induces oxidative stress in a rodent model of tauopathy. Eur J Neurosci 2006, 24: 1085–1090.PubMedGoogle Scholar
  84. [84]
    David DC, Hauptmann S, Scherping I, Schuessel K, Keil U, Rizzu P, et al. Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice. J Biol Chem 2005, 280: 23802–23814.PubMedGoogle Scholar
  85. [85]
    Dumont M, Stack C, Elipenahli C, Jainuddin S, Gerges M, Starkova NN, et al. Behavioral deficit, oxidative stress, and mitochondrial dysfunction precede tau pathology in P301S transgenic mice. FASEB J 2011, 25: 4063–4072.PubMedCentralPubMedGoogle Scholar
  86. [86]
    Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 2007, 53: 337–351.PubMedGoogle Scholar
  87. [87]
    Elipenahli C, Stack C, Jainuddin S, Gerges M, Yang L, Starkov A, et al. Behavioral improvement after chronic administration of coenzyme Q10 in P301S transgenic mice. J Alzheimers Dis 2012, 28: 173–182.PubMedCentralPubMedGoogle Scholar
  88. [88]
    Tuppo EE, Arias HR. The role of inflammation in Alzheimer’s disease. Int J Biochem Cell Biol 2005, 37: 289–305.PubMedGoogle Scholar
  89. [89]
    El Khoury J, Hickman SE, Thomas CA, Cao L, Silverstein SC, Loike JD. Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils. Nature 1996, 382: 716–719.PubMedGoogle Scholar
  90. [90]
    Johnstone M, Gearing AJ, Miller KM. A central role for astrocytes in the inflammatory response to beta-amyloid; chemokines, cytokines and reactive oxygen species are produced. J Neuroimmunol 1999, 93: 182–193.PubMedGoogle Scholar
  91. [91]
    Smits HA, Rijsmus A, van Loon JH, Wat JW, Verhoef J, Boven LA, et al. Amyloid-beta-induced chemokine production in primary human macrophages and astrocytes. J Neuroimmunol 2002, 127: 160–168.PubMedGoogle Scholar
  92. [92]
    Luo Y, Sunderland T, Roth GS, Wolozin B. Physiological levels of beta-amyloid peptide promote PC12 cell proliferation. Neurosci Lett 1996, 217: 125–128.PubMedGoogle Scholar
  93. [93]
    Kontush A, Schekatolina S. Vitamin E in Neurodegenerative Disorders: Alzheimer’s Disease. Ann N Y Acad Sci 2004, 1031: 249–262.PubMedGoogle Scholar
  94. [94]
    Puzzo D, Privitera L, Leznik E, Fa M, Staniszewski A, Palmeri A, et al. Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus. J Neurosci 2008, 28: 14537–14545.PubMedCentralPubMedGoogle Scholar
  95. [95]
    Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, et al. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 2001, 60: 759–767.PubMedGoogle Scholar
  96. [96]
    Nunomura A, Tamaoki T, Tanaka K, Motohashi N, Nakamura M, Hayashi T, et al. Intraneuronal amyloid beta accumulation and oxidative damage to nucleic acids in Alzheimer disease. Neurobiol Dis 2010, 37: 731–737.PubMedCentralPubMedGoogle Scholar
  97. [97]
    Castegna A, Aksenov M, Aksenova M, Thongboonkerd V, Klein JB, Pierce WM, et al. 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 2002, 33: 562–571.PubMedGoogle Scholar
  98. [98]
    Paola D, Domenicotti C, Nitti M, Vitali A, Borghi R, Cottalasso D, et al. Oxidative stress induces increase in intracellular amyloid beta-protein production and selective activation of betaI and betaII PKCs in NT2 cells. Biochem Biophys Res Commun 2000, 268: 642–646.PubMedGoogle Scholar
  99. [99]
    Nunomura A, Perry G, Pappolla MA, Friedland RP, Hirai K, Chiba S, et al. Neuronal oxidative stress precedes amyloidbeta deposition in Down syndrome. J Neuropathol Exp Neurol 2000, 59: 1011–1017.PubMedGoogle Scholar
  100. [100]
    Oda A, Tamaoka A, Araki W. Oxidative stress up-regulates presenilin 1 in lipid rafts in neuronal cells. J Neurosci Res 2010, 88: 1137–1145.PubMedGoogle Scholar
  101. [101]
    Tamagno E, Bardini P, Obbili A, Vitali A, Borghi R, Zaccheo D, et al. Oxidative stress increases expression and activity of BACE in NT2 neurons. Neurobiol Dis 2002, 10: 279–288.PubMedGoogle Scholar
  102. [102]
    Yoo MH, Gu X, Xu XM, Kim JY, Carlson BA, Patterson AD, et al. Delineating the role of glutathione peroxidase 4 in protecting cells against lipid hydroperoxide damage and in Alzheimer’s disease. Antioxid Redox Signal 2010, 12: 819–827.PubMedCentralPubMedGoogle Scholar
  103. [103]
    Tamagno E, Guglielmotto M, Aragno M, Borghi R, Autelli R, Giliberto L, et al. Oxidative stress activates a positive feedback between the γ- and β-secretase cleavages of the β-amyloid precursor protein. J Neurochem 2008, 104: 683–695.PubMedCentralPubMedGoogle Scholar
  104. [104]
    Cole GM, Teter B, Frautschy SA. Neuroprotective effects of curcumin. Adv Exp Med Biol 2007, 595: 197–212.PubMedCentralPubMedGoogle Scholar
  105. [105]
    Mandel SA, Amit T, Kalfon L, Reznichenko L, Youdim MB. Targeting multiple neurodegenerative diseases etiologies with multimodal-acting green tea catechins. J Nutr 2008, 138: 1578S–1583S.PubMedGoogle Scholar
  106. [106]
    Smith JV, Luo Y. Studies on molecular mechanisms of Ginkgo biloba extract. Appl Microbiol Biotechnol 2004, 64: 465–472.PubMedGoogle Scholar
  107. [107]
    Dumont M, Wille E, Stack C, Calingasan NY, Beal MF, Lin MT. 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 2009, 23: 2459–2466.PubMedCentralPubMedGoogle Scholar
  108. [108]
    Murakami K, Murata N, Noda Y, Tahara S, Kaneko T, Kinoshita N, et al. SOD1 (copper/zinc superoxide dismutase) deficiency drives amyloid beta protein oligomerization and memory loss in mouse model of Alzheimer disease. J Biol Chem 2011, 286: 44557–44568.PubMedCentralPubMedGoogle Scholar
  109. [109]
    Gamblin TC, King ME, Kuret J, Berry RW, Binder LI. Oxidative regulation of fatty acid-induced tau polymerization. Biochemistry 2000, 39: 14203–14210.PubMedGoogle Scholar
  110. [110]
    Schweers O, Mandelkow EM, Biernat J, Mandelkow E. Oxidation of cysteine-322 in the repeat domain of microtubule-associated protein tau controls the in vitro assembly of paired helical filaments. Proc Natl Acad Sci U S A 1995, 92: 8463–8467.PubMedCentralPubMedGoogle Scholar
  111. [111]
    Melov S, Adlard PA, Morten K, Johnson F, Golden TR, Hinerfeld D, et al. Mitochondrial oxidative stress causes hyperphosphorylation of tau. PLoS One 2007, 2: e536.PubMedCentralPubMedGoogle Scholar
  112. [112]
    Goedert M, Hasegawa M, Jakes R, Lawler S, Cuenda A, Cohen P. Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases. FEBS Lett 1997, 409: 57–62.PubMedGoogle Scholar
  113. [113]
    Wadsworth TL, Bishop JA, Pappu AS, Woltjer RL, Quinn JF. Evaluation of coenzyme Q as an antioxidant strategy for Alzheimer’s disease. J Alzheimer Dis 2008, 14: 225–234.Google Scholar
  114. [114]
    Yang X, Dai G, Li G, Yang E. Coenzyme Q10 reduces β-amyloid plaque in an APP/PS1 transgenic mouse model of Alzheimer’s disease. J Mol Neurosci 2010, 41: 110–113.PubMedGoogle Scholar
  115. [115]
    Yang X, Yang Y, Li G, Wang J, Yang E. Coenzyme Q10 attenuates β-amyloid pathology in the aged transgenic mice with Alzheimer Presenilin 1 mutation. J Mol Neurosci 2008, 34: 165–171.PubMedGoogle Scholar
  116. [116]
    Gutzmann H, Kuhl KP, Hadler D, Rapp MA. Safety and efficacy of idebenone versus tacrine in patients with Alzheimer’s disease: results of a randomized, double-blind, parallel-group multicenter study. Pharmacopsychiatry 2002, 35: 12–18.PubMedGoogle Scholar
  117. [117]
    Senin U, Parnetti L, Barbagallo-Sangiorgi G, Bartorelli L, Bocola V, Capurso A, et al. Idebenone in senile dementia of Alzheimer type: a multicentre study. Arch Gerontol Geriatr 1992, 15: 249–260.PubMedGoogle Scholar
  118. [118]
    Thal LJ, Grundman M, Berg J, Ernstrom K, Margolin R, Pfeiffer E, et al. Idebenone treatment fails to slow cognitive decline in Alzheimer’s disease. Neurology 2003, 61: 1498–1502.PubMedGoogle Scholar
  119. [119]
    Smith RAJ, Murphy MP. Animal and human studies with the mitochondria-targeted antioxidant MitoQ. Ann N Y Acad Sci 2010, 1201: 96–103.PubMedGoogle Scholar
  120. [120]
    Okun I, Tkachenko SE, Khvat A, Mitkin O, Kazey V, Ivachtchenko AV. From anti-allergic to anti-Alzheimer’s: molecular pharmacology of Dimebon. Curr Alzheimer Res 2010, 7: 97–112.PubMedGoogle Scholar
  121. [121]
    Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, et al. Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer’s disease: a randomised, doubleblind, placebo-controlled study. Lancet 2008, 372: 207–215.PubMedGoogle Scholar
  122. [122]
    Jones RW. Dimebon disappointment. Alzheimers Res Ther 2010, 2: 25.PubMedCentralPubMedGoogle Scholar
  123. [123]
    Baum L, Lam CW, Cheung SK, Kwok T, Lui V, Tsoh J, et al. Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. J Clin Psychopharmacol 2008, 28: 110–113.PubMedGoogle Scholar
  124. [124]
    Pettegrew JW, Klunk WE, Panchalingam K, Kanfer JN, McClure RJ. Clinical and neurochemical effects of acetyl-Lcarnitine in Alzheimer’s disease. Neurobiol Aging 1995, 16: 1–4.PubMedGoogle Scholar
  125. [125]
    Thal LJ, Carta A, Clarke WR, Ferris SH, Friedland RP, Petersen RC, et al. A 1-year multicenter placebo-controlled study of acetyl-L-carnitine in patients with Alzheimer’s disease. Neurology 1996, 47: 705–711.PubMedGoogle Scholar
  126. [126]
    Thal LJ, Calvani M, Amato A, Carta A, Group ftA-l-CS. A 1-year controlled trial of acetyl-l-carnitine in early-onset AD. Neurology 2000, 55: 805–810.PubMedGoogle Scholar
  127. [127]
    Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, et al. A Controlled Trial of selegiline, alphatocopherol, or both as treatment for Alzheimer’s disease. N Engl J Med1997, 336: 1216–1222.Google Scholar
  128. [128]
    Abramova NA, Cassarino DS, Khan SM, Painter TW, Bennett JP. Inhibition by R(+) or S(−) pramipexole of caspase activation and cell death induced by methylpyridinium ion or beta amyloid peptide in SH-SY5Y neuroblastoma. J Neurosci Res 2002, 67: 494–500.PubMedGoogle Scholar
  129. [129]
    Manczak M, Mao P, Calkins MJ, Cornea A, Reddy AP, Murphy MP, et al. Mitochondria-targeted antioxidants protect against amyloid-β toxicity in Alzheimer’s disease neurons. J Alzheimer Dis 2010, 20: 609–631.Google Scholar
  130. [130]
    Chen Z, Zhong C. Decoding Alzheimer’s disease from perturbed cerebral glucose metabolism: implications for diagnostic and therapeutic strategies. Prog Neurobiol 2013, 108: 21–43.PubMedGoogle Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS and Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of Neurology, Zhongshan Hospital; The State Key Laboratory of Medical NeurobiologyFudan UniversityShanghaiChina
  2. 2.The Institutes of Brain ScienceFudan UniversityShanghaiChina

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