Peripheral biomarkers of oxidative stress in aging and Alzheimer's disease

Marcourakis, Tania; Camarini, Rosana; Kawamoto, Elisa Mitiko; Scorsi, Leandro Rodrigues; Scavone, Cristoforo

doi:10.1590/S1980-57642009DN20100002

Abstract

Aging is associated with a greatly increased incidence of a number of neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). These conditions are associated with chronic inflammation, which generates oxygen reactive species, ultimately responsible for a process known as oxidative stress. It is well established that this process is the culprit of neurodegeneration, and there are also mounting evidences that it is not restricted to the central nervous system. Indeed, several studies, including some by our group, have demonstrated that increased peripheral oxidative stress markers are associated to aging and, more specifically, to AD. Therefore, it is very instigating to regard aging and AD as systemic conditions that might be determined by studying peripheral markers of oxidative stress.

Key words:
Alzheimer's disease; aging; oxidative stress; peripheral markers

Resumo

O envelhecimento está associado a uma alta incidência de doenças neurodegenerativas, incluindo doença de Alzheimer (DA), doença de Parkinson (DP) e esclerose lateral amiotrófica (ELA). Estas condições estão relacionadas à inflamação crônica que gera espécies reativas de oxigênio, responsáveis por um processo denominado de estresse oxidativo. Está bem estabelecido que este processo está envolvido na neurodegeneração, e existem várias evidências de que ele não é restrito ao sistema nervoso central. De fato, muitos estudos, inclusive alguns de nosso grupo, demonstraram que o aumento de marcadores do estresse oxidativo periférico está associado ao envelhecimento e, mais intensamente, à DA. Assim, é muito instigante pensar no envelhecimento e na DA como doenças sistêmicas que possam ser investigadas por meio de marcadores periféricos de estresse oxidativo.

Palavras-chave:
doença de Alzheimer; envelhecimento; estresse oxidativo; marcadores periféricos

Texto completo disponível apenas em PDF.

Full text available only in PDF format.

Acknowledgements

The authors thank Fernando Kok for his helpful comments. CS is supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); EMK, by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) and LRS by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). Work in the laboratory of the authors was supported by FAPESP.

References

¹
Harman D. The aging process. Proc Natl Acad Sci USA 1981; 78:7124-7128.
²
Harman D. Free-radical theory of aging. Increasing the functional life span. Ann N Y Acad Sci 1994;717:1-15.
³
Harman D. Aging: phenomena and theories. Ann N Y Acad Sci 1998;854:1-7.
⁴
Yu BP. Aging and oxidative stress: modulation by dietary restriction. Free Radical Biol Med 1996;21:651-668.
⁵
Floyd RA. Antioxidants, oxidative stress, and degenerative neurological disorders. Proc Soc Exp Biol Med 1999;222:236-245.
⁶
Maccioni RB, Munoz JP, Barbeito L. The molecular bases of Alzheimer's disease and other neurodegenerative disorders. Arch Med Res 2001;32:367-381.
⁷
Mark RJ, Blanc EM, Mattson MP. Amyloid beta-peptide and oxidative cellular injury in Alzheimer's disease. Mol Neurobiol 1996;12:211-224.
⁸
Smith CD, Carney JM, Starke-Reed PE, et al. Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. Proc Natl Acad Sci USA 1991;88:10540-10543.
⁹
Wimo A, Winblad B, Aguero-Torres H, von Strauss E. The magnitude of dementia occurrence in the world. Alz Dis Assoc Dis 2003;17:63-67.
¹⁰
Medvedev ZA. An attempt at a rational classification of theories of ageing. Biol Rev Camb Philos Soc 1990;65:375-398.
¹¹
Halliwell B, Gutteridge JMC. Free radical in Biology and Medicine. 4th: New York, Oxford University Press; 2007.
¹²
Kasapoglu M, Özben T. Alterations of antioxidant enzymes and oxidative stress markers in aging. Exp Geront 2001;36:209-220.
¹³
Praticò D, Delanty N. Oxidative injury in diseases of the central nervous system: focus on Alzheimer's disease. Am J Med 2000;109:577-585.
¹⁴
Mamelak M. Alzheimer's disease, oxidative stress and gammahydroxybutyrate. Neurobiol Aging 2007;28:1340-1360.
¹⁵
Valko M, Leibfritz D, Moncol J, Cronin MTD, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 2007;39:44-84.
¹⁶
Floyd RA. Neuroinflammatory processes are important in neurodegenerative diseases: a hypothesis to explain the increased formation of reactive oxygen and nitrogen species as major factors involved in neurodegenerative disease development. Free Rad Biol Med 1999;26:1346-1355.
¹⁷
Markesberry WR. The role of oxidative stress in Alzheimer Disease. Arch Neurol 1999;56:1449-1452.
¹⁸
Slivka A, Mytilineou C, Cohen G. Histochemical evaluation of glutathione in brain. Brain Res 1987;409:275-284.
¹⁹
Lipton SA, Choi YB, Pan ZH, et al. A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 1993;364:626-632.
²⁰
Beckman JS, Koppenol WH. Nitric oxide, superoxide and peroxynitrite: the good, the bad and ugly. Am J Physiol 1996;271:C1424-C1437.
²¹
Bolanos JP, Almeida A, Stewart V, et al. Nitric oxide-mediated mitochondrial damage in the brain: mechanisms and implications for neurodegenerative diseases. J Neurochem 1997;68:2227-2240.
²²
Markesberry WR, Carney JM. Oxidative alternations in Alzheimer's disease. Brain Pathol 1999;9:133-146.
²³
Harman D. Free radical theory of aging: Alzheimer's disease pathogenesis. Age 1995;18:97-119.
²⁴
Harman D. Alzheimer's disease: role of aging in pathogenesis. Ann N Y Acad Sci 2002;959:384-395.
²⁵
Selkoe DJ. Translating cell biology into therapeutic advances in Alzheimer's disease. Nature 1999;399:A23-A31.
²⁶
Lue LF, Brachova L, Civin WH, Rogers J. Inflammation, Ab deposition, and neurofibrillary tangle formation as correlates of Alzheimer's disease neurodegeneration. J Neuropathol Exp Neurol 1996;55:1083-1088.
²⁷
Teunissen CE, Lütjohann D, von Bergmann K, et al. Combination of serum markers related to several mechanisms in Alzheimer's disease. Neurobiol Aging 2003;24:893-902.
²⁸
Zhu X, Su B, Wang X, Smith MA, Perry G. Causes of oxidative stress in Alzheimer disease. Cell Mol Life Sci 2007;64:2202-2210.
²⁹
Smith CD, Carney JM, Starke-Reed PE, et al. Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. Proc Natl Acad Sci USA 1991;88:10540-10543.
³⁰
Swerdlow RH. Is aging part of Alzheimer's disease, or is Alzheimer's disease part of aging? Neurobiol Aging 2007;28: 1465:1480.
³¹
Butterfield DA. Beta-Amyloid-associated free radical oxidative stress and neurotoxicity: implications for Alzheimer's disease. Chem Res Toxicol 1997;10:495-506.
³²
Butterfield DA, Yatin SM, Varadarajan S, Koppal T. Amyloid b-peptide-associated free radical oxidative stress, neurotoxicity and Alzheimer's disease. Methods Enzymol 1999;309:746-768.
³³
Knight J. Free radicals: their history and current status in aging and disease. J Clin Lab Sci 1998;28:331-346.
³⁴
Olanow CW. A radical hypothesis for neurodegeneration. Trends Neurosci 1993;16:339-444.
³⁵
Migliore L, Fontana I, Trippi F, et al. Oxidative DNA damage in peripheral leukocytes of mild cognitive impairment and AD patients. Neurobiol Aging 2005;26:567-573.
³⁶
Nunomura A, Perry G, Aliev G, et al. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 2001;60:759-767.
³⁷
Praticó D, Uryu K, Leight S, Trojanoswki JQ, Lee VM. Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J Neurosci 2001;21:4183-4187.
³⁸
Smith MA, Rottkamp CA, Nunomura A, Raina AK, Perry G. Oxidative stress in Alzheimer´s disease. Biochem Biophys Acta 2000;1502:139-144.
³⁹
Veurink G, Fuller SJ, Atwood CS, Martins RN. Genetics, lifestyle and the roles of amyloid beta and oxidative stress in Alzheimer´s disease. Ann Hum Biol 2003;30:639-667.
⁴⁰
Pike CJ, Ramezan-Arab N, Cotman CW. b-Amyloid neurotoxicity in vitro: evidence of oxidative stress but not protection by antioxidants. J Neurochem 1997;69:1601-1611.
⁴¹
Hensley K, Hall N, Shaw W, Carney JM, Butterfield DA. Electron paramagnetic resonance investigation of free radical induced alterations in neocortical synaptosomal membrane protein infrastructure. Free Rad Biol Med 1994; 17:321-331.
⁴²
Varadarajan S, Yatin S, Aksenova M, Butterfield DA. Review: Alzheimer's amyloid b-peptide- associated free radical oxidative stress and neurotoxicity. J Struct Biol 2000;130:184-208.
⁴³
Crouch PJ, Harding S-ME, White AR, Camakaris J, Bush AI, Masters CL. Mechanisms of Ab mediated neurodegeneration in Alzheimer's disease. Int J Biochem Cell Biol 2008;40:181-198.
⁴⁴
De Felice F, Velasco PT, Lambert MP, et al. Ab oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J Biol Chem 2007; 282:11590-11601.
⁴⁵
Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid b-peptide. Nat Rev Mol Cell Biol 2007; 8:101-112.
⁴⁶
Ferreira ST, Vieira MNN, De Felice F. Soluble protein oligomers as emerging toxins in Alzheimer's and other amyloid diseases. IUBMB Life 2007;59:199-210.
⁴⁷
Özdemir S, Yargiçoglu P, Agar A, Gümüslü S, Bîlmen S, Hacioglu G. Role of nitric oxide on age-dependent alterations: investigation of electrophysiologic and biochemical parameters. Intern J Neuroscience 2002;112:263-276.
⁴⁸
Goldstein IM, Ostwald P, Roth S. Nitric oxide: a review of its role in retinal function and disease. Vision Res 1996;26:2979-2994.
⁴⁹
Oku H, Yamaguchi H, Sugiyama T, Kojima S, Ota M, Azuma I. Retinal toxicity of nitric oxide released by administration of a nitric oxide donor in the albino rabit. Invest Ophthalm Visual Sci 1997;38:2540-2544.
⁵⁰
Wink DA, Cook JA, Pacelli R, et al. The effects of various nitric oxide-donor agents on hydrogen peroxide toxicity: a direct correlation between nitric oxide formation and protection. Arch Biochem Biophys 1996;331:241-248.
⁵¹
Kashii S, Mandai M, Kikuchi M, et al. Dual actions of nitric oxide in N-methyl-D-aspartate receptor-mediated neurotoxicity in cultures retinal neurons. Brain Res 1996;711:93-101.
⁵²
O'Donnell VB, Chumley PH, Hogg N, Bloodsworth A, Darley-Usmar VM, Freeman BA. Nitric oxide inhibition of lipid peroxidation. Kinetics of reaction with lipid peroxyl radicals and comparison with a-tocopherol. Biochemistry 1997;36:15216-15223.
⁵³
Cudeiro J, Rivadulla C. Sight and insight on the physiological role of nitric oxide in the visual system. Trends Neurosci 1999;22:109-116.
⁵⁴
Gibson GE, Huang H-M. Oxidative stress in Alzheimer's disease. Neurobiol Aging 2005;26:575-578.
⁵⁵
Praticó D. Peripheral biomarkers of oxidative damage in Alzheimers disease: the road ahead. Neurobiol Aging 2005;26: 581-583.
⁵⁶
Smith MA, Nunomura A, Lee H-g, et al. Chronological primacy of oxidative stress in Alzheimer disease. Neubiol Aging 2005;26:579-580.
⁵⁷
Solichova D, Juraskova B, Blaha V, et al. Bioanalysis of age-related changes of lipid metabolism in nonagenarians. J Pharm Biomed Anal 2001;24:1157-1162.
⁵⁸
Guemouri L, Artur Y, Herbeth B, Jeandel C, Cuny G, Siest G. Biological variability of superoxide dismutase, glutathione peroxidase and catalase in blood. Clin Chem 1991;37:1932-1937.
⁵⁹
King CM, Barnett YA. Oxidative stress and human ageing. Biochem Soc Trans 1995;23:375S.
⁶⁰
Junqueira VBC, Barros SBM, Chan SS, Rodrigues L, Giavavarotti L, Abud RL, Deucher GP. Aging and oxidative stress. Mol Aspects Med 2004;25:5-16.
⁶¹
Mecocci P, Polidori MC, Troiano L, et al. Plasma antioxidants and longevity: a study on healthy centenarians. Free Rad Biol Med 2000;28:1243-1248.
⁶²
Andersen HR, Jeune B, Nybo H, Nielsen JB, Andersen-Ranberg K, Grandjean P. Low activity of superoxide dismutase and high activity of glutathione reductase in erythrocytes from centenarians. Age Aging 1998;27:643-648.
⁶³
Paolisso G, Tagliamonte MR, Rizzo MR, Manzella D, Gambardella A, Varricchio M. Oxidative stress and advancing age: results in healthy centenarians. J Am Geriatr Soc 1998;46: 833-838.
⁶⁴
Ahlskog JE, Uitti RJ, Low PA, et al. No evidence for systemic oxidant stress in Parkinson's or Alzheimer's disease. Mov Dis 1995;10:566-573.
⁶⁵
Kawamoto EM, Munhoz CD, Glezer I, et al. Oxidative stress in platelets and erythrocytes in aging and Alzheimer's disease. Neurobiol Aging 2005;26:857-864.
⁶⁶
Gloor SM. Relevance of Na,K-ATPase to local extracellular potassium homeostasis and modulation of synaptic transmission. FEBS Lett 1997;412:1-4.
⁶⁷
Kim MS, Akera T. O2 free radicals: cause of ischemia-reperfusion injury to cardiac Na+-K+-ATPase. Am J Physiol 1987;252:H252-H257.
⁶⁸
Mense M, Stark G, Apell HJ. Effects of free radicals on partial reactions of the Na,K-ATPase. J Membr Biol 1997;156:63-71.
⁶⁹
Xie Z, Jack-Hays M, Wang Y, et al. Different oxidant sensitivities of the alpha 1 and alpha 2 isoforms of Na/K-ATPase expressed in baculovirus-infected insect cells. Biochem Biophys Res Commun 1995;207:155-159.
⁷⁰
Praticó D, Clark CM, Lee VMY, Trojanowski JQ, Rokach J, FitzGerald GA. Increased 8,12-iso-iPF2a-VI in Alzheimer's disease: correlation of a noninvasive index of lipid peroxidation with disease severity. Ann Neurol 2000;48:809-812.
⁷¹
Aybeck H, Ercan F, Aslan D, Sahiner T. Determination of malondialdehyde, reduced glutathione levels and APOE4 allele frequency in late-onset Alzheimer's disease in Denizli, Turkey. Clin Biochem 2007;40:172-176.
⁷²
Bourdel-Marchasson I, Delmas-Beauvieux M-C, Peuchant E, et al. Antioxidant defences and oxidative stress markers in erythrocytes and plasma from normally nourished elderly Alzheimer patients. Age Aging 2001;30:235-241.
⁷³
Delibas M, Ozcankaya R, Altuntas I. Clinical importance of erythrocyte malondialdehyde levels as a marker for cognitive deterioration in patients with dementia of Alzheimer type: a repeated study in 5-year interval. Clin Biochem 2002;32:137-141.
⁷⁴
Zafrilla P, Mulero J, Xandri JM, Santo E, Caravaca G, Morillas JM. Oxidative stress in Alzheimer patients in different stages of the disease. Curr Med Chem 2006;13:1075-1083.
⁷⁵
Meccocci P, Polidori MC, Cherubini A, et al. Lymphocyte oxidative DNA damage and plasma antioxidants in Alzheimer disease. Arch Neurol 2002;59:794-798.
⁷⁶
Rinaldi P, Polidori MC, Metastasio A, et al. Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer´s disease. Neurobiol Aging 2003;24:915-919.
⁷⁷
Gackowski D, Rozalski R, Siomek A, et al. Oxidative stress and oxidative DNA damage is characteristic for mixed Alzheimer disease/vascular dementia. J Neuro Sci 2008;266:57-62.
⁷⁸
Engelhart MJ, Geerlings MI, Ruitenberg A, et al. Dietary intake of antioxidants and risk of Alzheimer disease. JAMA 2002;287:3223-3229.
⁷⁹
Luchsinger JA, Tang MX, Shea S, Mayeux R. Antioxidant vitamin intake and risk of Alzheimer disease. Arch Neurol 2003;60:203-208.
⁸⁰
Morris MC, Evans DA, Bienias JL, et al. Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. JAMA 2002;287:3230-3237.
⁸¹
Cole GM, Morihara T, Lim GP, Yang F, Bequm A, Frautschy SA. NSAID and antioxidant prevention of Alzheimer´s disease: lessons from in vitro and animal models. Ann. N.Y.Acad Sci 2004;1025:68-84.
⁸²
Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37-46.

Publication Dates

Publication in this collection
Jan-Mar 2008

History

Received
24 Jan 2008
Reviewed
14 Feb 2008
Accepted
14 Feb 2008

This is an open-access article distributed under the terms of the Creative Commons Attribution License

[1] ¹
Harman D. The aging process. Proc Natl Acad Sci USA 1981; 78:7124-7128.

[2] ²
Harman D. Free-radical theory of aging. Increasing the functional life span. Ann N Y Acad Sci 1994;717:1-15.

[3] ³
Harman D. Aging: phenomena and theories. Ann N Y Acad Sci 1998;854:1-7.

[4] ⁴
Yu BP. Aging and oxidative stress: modulation by dietary restriction. Free Radical Biol Med 1996;21:651-668.

[5] ⁵
Floyd RA. Antioxidants, oxidative stress, and degenerative neurological disorders. Proc Soc Exp Biol Med 1999;222:236-245.

[6] ⁶
Maccioni RB, Munoz JP, Barbeito L. The molecular bases of Alzheimer's disease and other neurodegenerative disorders. Arch Med Res 2001;32:367-381.

[7] ⁷
Mark RJ, Blanc EM, Mattson MP. Amyloid beta-peptide and oxidative cellular injury in Alzheimer's disease. Mol Neurobiol 1996;12:211-224.

[8] ⁸
Smith CD, Carney JM, Starke-Reed PE, et al. Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. Proc Natl Acad Sci USA 1991;88:10540-10543.

[9] ⁹
Wimo A, Winblad B, Aguero-Torres H, von Strauss E. The magnitude of dementia occurrence in the world. Alz Dis Assoc Dis 2003;17:63-67.

[10] ¹⁰
Medvedev ZA. An attempt at a rational classification of theories of ageing. Biol Rev Camb Philos Soc 1990;65:375-398.

[11] ¹¹
Halliwell B, Gutteridge JMC. Free radical in Biology and Medicine. 4th: New York, Oxford University Press; 2007.

[12] ¹²
Kasapoglu M, Özben T. Alterations of antioxidant enzymes and oxidative stress markers in aging. Exp Geront 2001;36:209-220.

[13] ¹³
Praticò D, Delanty N. Oxidative injury in diseases of the central nervous system: focus on Alzheimer's disease. Am J Med 2000;109:577-585.

[14] ¹⁴
Mamelak M. Alzheimer's disease, oxidative stress and gammahydroxybutyrate. Neurobiol Aging 2007;28:1340-1360.

[15] ¹⁵
Valko M, Leibfritz D, Moncol J, Cronin MTD, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 2007;39:44-84.

[16] ¹⁶
Floyd RA. Neuroinflammatory processes are important in neurodegenerative diseases: a hypothesis to explain the increased formation of reactive oxygen and nitrogen species as major factors involved in neurodegenerative disease development. Free Rad Biol Med 1999;26:1346-1355.

[17] ¹⁷
Markesberry WR. The role of oxidative stress in Alzheimer Disease. Arch Neurol 1999;56:1449-1452.

[18] ¹⁸
Slivka A, Mytilineou C, Cohen G. Histochemical evaluation of glutathione in brain. Brain Res 1987;409:275-284.

[19] ¹⁹
Lipton SA, Choi YB, Pan ZH, et al. A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 1993;364:626-632.

[20] ²⁰
Beckman JS, Koppenol WH. Nitric oxide, superoxide and peroxynitrite: the good, the bad and ugly. Am J Physiol 1996;271:C1424-C1437.

[21] ²¹
Bolanos JP, Almeida A, Stewart V, et al. Nitric oxide-mediated mitochondrial damage in the brain: mechanisms and implications for neurodegenerative diseases. J Neurochem 1997;68:2227-2240.

[22] ²²
Markesberry WR, Carney JM. Oxidative alternations in Alzheimer's disease. Brain Pathol 1999;9:133-146.

[23] ²³
Harman D. Free radical theory of aging: Alzheimer's disease pathogenesis. Age 1995;18:97-119.

[24] ²⁴
Harman D. Alzheimer's disease: role of aging in pathogenesis. Ann N Y Acad Sci 2002;959:384-395.

[25] ²⁵
Selkoe DJ. Translating cell biology into therapeutic advances in Alzheimer's disease. Nature 1999;399:A23-A31.

[26] ²⁶
Lue LF, Brachova L, Civin WH, Rogers J. Inflammation, Ab deposition, and neurofibrillary tangle formation as correlates of Alzheimer's disease neurodegeneration. J Neuropathol Exp Neurol 1996;55:1083-1088.

[27] ²⁷
Teunissen CE, Lütjohann D, von Bergmann K, et al. Combination of serum markers related to several mechanisms in Alzheimer's disease. Neurobiol Aging 2003;24:893-902.

[28] ²⁸
Zhu X, Su B, Wang X, Smith MA, Perry G. Causes of oxidative stress in Alzheimer disease. Cell Mol Life Sci 2007;64:2202-2210.

[29] ²⁹
Smith CD, Carney JM, Starke-Reed PE, et al. Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. Proc Natl Acad Sci USA 1991;88:10540-10543.

[30] ³⁰
Swerdlow RH. Is aging part of Alzheimer's disease, or is Alzheimer's disease part of aging? Neurobiol Aging 2007;28: 1465:1480.

[31] ³¹
Butterfield DA. Beta-Amyloid-associated free radical oxidative stress and neurotoxicity: implications for Alzheimer's disease. Chem Res Toxicol 1997;10:495-506.

[32] ³²
Butterfield DA, Yatin SM, Varadarajan S, Koppal T. Amyloid b-peptide-associated free radical oxidative stress, neurotoxicity and Alzheimer's disease. Methods Enzymol 1999;309:746-768.

[33] ³³
Knight J. Free radicals: their history and current status in aging and disease. J Clin Lab Sci 1998;28:331-346.

[34] ³⁴
Olanow CW. A radical hypothesis for neurodegeneration. Trends Neurosci 1993;16:339-444.

[35] ³⁵
Migliore L, Fontana I, Trippi F, et al. Oxidative DNA damage in peripheral leukocytes of mild cognitive impairment and AD patients. Neurobiol Aging 2005;26:567-573.

[36] ³⁶
Nunomura A, Perry G, Aliev G, et al. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 2001;60:759-767.

[37] ³⁷
Praticó D, Uryu K, Leight S, Trojanoswki JQ, Lee VM. Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J Neurosci 2001;21:4183-4187.

[38] ³⁸
Smith MA, Rottkamp CA, Nunomura A, Raina AK, Perry G. Oxidative stress in Alzheimer´s disease. Biochem Biophys Acta 2000;1502:139-144.

[39] ³⁹
Veurink G, Fuller SJ, Atwood CS, Martins RN. Genetics, lifestyle and the roles of amyloid beta and oxidative stress in Alzheimer´s disease. Ann Hum Biol 2003;30:639-667.

[40] ⁴⁰
Pike CJ, Ramezan-Arab N, Cotman CW. b-Amyloid neurotoxicity in vitro: evidence of oxidative stress but not protection by antioxidants. J Neurochem 1997;69:1601-1611.

[41] ⁴¹
Hensley K, Hall N, Shaw W, Carney JM, Butterfield DA. Electron paramagnetic resonance investigation of free radical induced alterations in neocortical synaptosomal membrane protein infrastructure. Free Rad Biol Med 1994; 17:321-331.

[42] ⁴²
Varadarajan S, Yatin S, Aksenova M, Butterfield DA. Review: Alzheimer's amyloid b-peptide- associated free radical oxidative stress and neurotoxicity. J Struct Biol 2000;130:184-208.

[43] ⁴³
Crouch PJ, Harding S-ME, White AR, Camakaris J, Bush AI, Masters CL. Mechanisms of Ab mediated neurodegeneration in Alzheimer's disease. Int J Biochem Cell Biol 2008;40:181-198.

[44] ⁴⁴
De Felice F, Velasco PT, Lambert MP, et al. Ab oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J Biol Chem 2007; 282:11590-11601.

[45] ⁴⁵
Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid b-peptide. Nat Rev Mol Cell Biol 2007; 8:101-112.

[46] ⁴⁶
Ferreira ST, Vieira MNN, De Felice F. Soluble protein oligomers as emerging toxins in Alzheimer's and other amyloid diseases. IUBMB Life 2007;59:199-210.

[47] ⁴⁷
Özdemir S, Yargiçoglu P, Agar A, Gümüslü S, Bîlmen S, Hacioglu G. Role of nitric oxide on age-dependent alterations: investigation of electrophysiologic and biochemical parameters. Intern J Neuroscience 2002;112:263-276.

[48] ⁴⁸
Goldstein IM, Ostwald P, Roth S. Nitric oxide: a review of its role in retinal function and disease. Vision Res 1996;26:2979-2994.

[49] ⁴⁹
Oku H, Yamaguchi H, Sugiyama T, Kojima S, Ota M, Azuma I. Retinal toxicity of nitric oxide released by administration of a nitric oxide donor in the albino rabit. Invest Ophthalm Visual Sci 1997;38:2540-2544.

[50] ⁵⁰
Wink DA, Cook JA, Pacelli R, et al. The effects of various nitric oxide-donor agents on hydrogen peroxide toxicity: a direct correlation between nitric oxide formation and protection. Arch Biochem Biophys 1996;331:241-248.

[51] ⁵¹
Kashii S, Mandai M, Kikuchi M, et al. Dual actions of nitric oxide in N-methyl-D-aspartate receptor-mediated neurotoxicity in cultures retinal neurons. Brain Res 1996;711:93-101.

[52] ⁵²
O'Donnell VB, Chumley PH, Hogg N, Bloodsworth A, Darley-Usmar VM, Freeman BA. Nitric oxide inhibition of lipid peroxidation. Kinetics of reaction with lipid peroxyl radicals and comparison with a-tocopherol. Biochemistry 1997;36:15216-15223.

[53] ⁵³
Cudeiro J, Rivadulla C. Sight and insight on the physiological role of nitric oxide in the visual system. Trends Neurosci 1999;22:109-116.

[54] ⁵⁴
Gibson GE, Huang H-M. Oxidative stress in Alzheimer's disease. Neurobiol Aging 2005;26:575-578.

[55] ⁵⁵
Praticó D. Peripheral biomarkers of oxidative damage in Alzheimers disease: the road ahead. Neurobiol Aging 2005;26: 581-583.

[56] ⁵⁶
Smith MA, Nunomura A, Lee H-g, et al. Chronological primacy of oxidative stress in Alzheimer disease. Neubiol Aging 2005;26:579-580.

[57] ⁵⁷
Solichova D, Juraskova B, Blaha V, et al. Bioanalysis of age-related changes of lipid metabolism in nonagenarians. J Pharm Biomed Anal 2001;24:1157-1162.

[58] ⁵⁸
Guemouri L, Artur Y, Herbeth B, Jeandel C, Cuny G, Siest G. Biological variability of superoxide dismutase, glutathione peroxidase and catalase in blood. Clin Chem 1991;37:1932-1937.

[59] ⁵⁹
King CM, Barnett YA. Oxidative stress and human ageing. Biochem Soc Trans 1995;23:375S.

[60] ⁶⁰
Junqueira VBC, Barros SBM, Chan SS, Rodrigues L, Giavavarotti L, Abud RL, Deucher GP. Aging and oxidative stress. Mol Aspects Med 2004;25:5-16.

[61] ⁶¹
Mecocci P, Polidori MC, Troiano L, et al. Plasma antioxidants and longevity: a study on healthy centenarians. Free Rad Biol Med 2000;28:1243-1248.

[62] ⁶²
Andersen HR, Jeune B, Nybo H, Nielsen JB, Andersen-Ranberg K, Grandjean P. Low activity of superoxide dismutase and high activity of glutathione reductase in erythrocytes from centenarians. Age Aging 1998;27:643-648.

[63] ⁶³
Paolisso G, Tagliamonte MR, Rizzo MR, Manzella D, Gambardella A, Varricchio M. Oxidative stress and advancing age: results in healthy centenarians. J Am Geriatr Soc 1998;46: 833-838.

[64] ⁶⁴
Ahlskog JE, Uitti RJ, Low PA, et al. No evidence for systemic oxidant stress in Parkinson's or Alzheimer's disease. Mov Dis 1995;10:566-573.

[65] ⁶⁵
Kawamoto EM, Munhoz CD, Glezer I, et al. Oxidative stress in platelets and erythrocytes in aging and Alzheimer's disease. Neurobiol Aging 2005;26:857-864.

[66] ⁶⁶
Gloor SM. Relevance of Na,K-ATPase to local extracellular potassium homeostasis and modulation of synaptic transmission. FEBS Lett 1997;412:1-4.

[67] ⁶⁷
Kim MS, Akera T. O2 free radicals: cause of ischemia-reperfusion injury to cardiac Na+-K+-ATPase. Am J Physiol 1987;252:H252-H257.

[68] ⁶⁸
Mense M, Stark G, Apell HJ. Effects of free radicals on partial reactions of the Na,K-ATPase. J Membr Biol 1997;156:63-71.

[69] ⁶⁹
Xie Z, Jack-Hays M, Wang Y, et al. Different oxidant sensitivities of the alpha 1 and alpha 2 isoforms of Na/K-ATPase expressed in baculovirus-infected insect cells. Biochem Biophys Res Commun 1995;207:155-159.

[70] ⁷⁰
Praticó D, Clark CM, Lee VMY, Trojanowski JQ, Rokach J, FitzGerald GA. Increased 8,12-iso-iPF2a-VI in Alzheimer's disease: correlation of a noninvasive index of lipid peroxidation with disease severity. Ann Neurol 2000;48:809-812.

[71] ⁷¹
Aybeck H, Ercan F, Aslan D, Sahiner T. Determination of malondialdehyde, reduced glutathione levels and APOE4 allele frequency in late-onset Alzheimer's disease in Denizli, Turkey. Clin Biochem 2007;40:172-176.

[72] ⁷²
Bourdel-Marchasson I, Delmas-Beauvieux M-C, Peuchant E, et al. Antioxidant defences and oxidative stress markers in erythrocytes and plasma from normally nourished elderly Alzheimer patients. Age Aging 2001;30:235-241.

[73] ⁷³
Delibas M, Ozcankaya R, Altuntas I. Clinical importance of erythrocyte malondialdehyde levels as a marker for cognitive deterioration in patients with dementia of Alzheimer type: a repeated study in 5-year interval. Clin Biochem 2002;32:137-141.

[74] ⁷⁴
Zafrilla P, Mulero J, Xandri JM, Santo E, Caravaca G, Morillas JM. Oxidative stress in Alzheimer patients in different stages of the disease. Curr Med Chem 2006;13:1075-1083.

[75] ⁷⁵
Meccocci P, Polidori MC, Cherubini A, et al. Lymphocyte oxidative DNA damage and plasma antioxidants in Alzheimer disease. Arch Neurol 2002;59:794-798.

[76] ⁷⁶
Rinaldi P, Polidori MC, Metastasio A, et al. Plasma antioxidants are similarly depleted in mild cognitive impairment and in Alzheimer´s disease. Neurobiol Aging 2003;24:915-919.

[77] ⁷⁷
Gackowski D, Rozalski R, Siomek A, et al. Oxidative stress and oxidative DNA damage is characteristic for mixed Alzheimer disease/vascular dementia. J Neuro Sci 2008;266:57-62.

[78] ⁷⁸
Engelhart MJ, Geerlings MI, Ruitenberg A, et al. Dietary intake of antioxidants and risk of Alzheimer disease. JAMA 2002;287:3223-3229.

[79] ⁷⁹
Luchsinger JA, Tang MX, Shea S, Mayeux R. Antioxidant vitamin intake and risk of Alzheimer disease. Arch Neurol 2003;60:203-208.

[80] ⁸⁰
Morris MC, Evans DA, Bienias JL, et al. Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. JAMA 2002;287:3230-3237.

[81] ⁸¹
Cole GM, Morihara T, Lim GP, Yang F, Bequm A, Frautschy SA. NSAID and antioxidant prevention of Alzheimer´s disease: lessons from in vitro and animal models. Ann. N.Y.Acad Sci 2004;1025:68-84.

[82] ⁸²
Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37-46.

Brasil