Abstract
Accumulating data from experimental and human studies indicate that oxidative stress (OS) plays a major role in the pathogenesis of Alzheimer’s disease (AD). The production of reactive oxygen species (ROS), which leads to OS, can occur very early, even before the appearance of symptoms and molecular events (β-amyloid plaques and neurofibrillary tangles), leading to tissue damage via several different cellular molecular pathways. ROS can cause damage to cardinal cellular components such as lipids, proteins, and nucleic acids (e.g., RNA, DNA), causing cell death by modes of necrosis or apoptosis. The damage can become more widespread because of the weakened cellular antioxidant defense systems. Therefore, treatment with antioxidants might theoretically act to prevent propagation of tissue damage and improve both survival and neurological outcome. Indeed, several studies preformed to date examined whether dietary intake of several antioxidants, mainly vitamins, might prevent or reduce the progression of AD. Although a few of the antioxidants showed some efficacy in these trials, no answer is yet available as to whether antioxidants are truly protective against AD. Reasons for these results might include, in part, blood-brain barrier (BBB) permeability, inappropriate timing of administration, or suboptimal drug levels at the target site in the central nervous system. Thus, antioxidant cocktails or antioxidants combined with other drugs may have more successful synergistic effects. Further, well-designed intervention, as well as observational investigations based on large cohorts studied over a long period of time with several methods for assessing antioxidant exposure, including relation to BBB penetration, are needed to test this hypothesis.
Similar content being viewed by others
References
Beal M. F. (1995) Aging, energy and OS in neurodegenerative diseases. Ann. Neurol. 38, 357–366.
Beal M. F. (1996) Mitochondria, free radicals, and neurodegeneration. Curr. Opin. Neurobiol. 46, 661–666.
Burns A. and Zaudig M. (2002) Mild cognitive impairment in older people. Lancet 360, 1963–1965.
Butterfield D. A., Drake J., Pocernich C., et al. (2001) Evidence of oxidative damage in Alzheimer’s disease brain: central role for amyloid beta-peptide. Trends Mol. Med. 7, 548–554.
Christen Y. (2000) Oxidative stress and Alzheimer disease. Am. J. Clin. Nutr. 71, 621S-629S.
Clark C. M. (2000) Clinical manifestation and diagnostic evaluation of patients with Alzheimer’s disease, in Neurodegenerative Dementias: Clinical Features and Pathological Mechanisms, Clark C. M. and Trojanowski J. Q., eds. McGraw-Hill, New York, pp. 95–114.
Commenges D., Scotet V., Renaud S., et al. (2000) Intake of flavonoids and risk of dementia. Eur. J. Epidemiol. 16, 357–363.
Crapper D. R., Quittkat S., Krishnan S. S., et al. (1980) Intracellular aluminum content in Alzheimer disease, dialysis encephalopathy, and experimental aluminum encephalopathy. Neuropathology (Berl.) 50, 19–24.
Cummings J. F. and Cole G. (2002) Alzheimer disease. JAMA 287, 2335–2338.
Cummings J. F., Frank J. C., Cherry D., et al. (2002) Guidelines for managing Alzheimer’s disease: Part II. Treatment. Am. Fam. Physician 65, 2263–2272.
Cutler R. G. (1991) Human longevity and aging: possible role of reactive oxygen species. Ann. N. Y. Acad. Sci. 621, 1–28.
Danysz W., Parsons C. G., Bresink I., et al. (1995) Glutamate in CNS disorders: A revived target for drug development. Drugs News Pers. 8, 261–277.
Deibel M. A., Ehmann W. D., and Markesbery W. R. (1997) Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer disease: possible relation to oxidative stress. J. Neurol. Sci. 143, 137–142.
Doble A. (1999) The role of excitotoxicity in neurodegenerative disease: implications for therapy. Pharmacol. Ther. 81, 163–221.
Engelhart N. U., Geerlings M. I., Ruitenberg A., et al. (2002) Dietary intake of antioxidants and risk of Alzheimer disease. JAMA 287, 3223–3229.
Fassbender K., Simons M., Bergmann C., et al. (2001) Simvastatin strongly reduces levels of Alzheimer’s disease beta-amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc. Natl. Acad. Sci. U. S. A. 98, 5856–5861.
Flynn B. L. and Ranno A. E. (1999) Pharmacologic management of Alzheimer disease. Part II: Antioxidants, antihyprtensives, and ergolid derivatives. Ann. Pharmacother. 33, 188–197.
Fukagawa N. K. (1999) Aging: is oxidative stress a marker or is it causal? Proc. Soc. Exp. Biol. Med. 222, 293–298.
Gilgun-Sherki Y., Melamed E., and Offen D. (2001) Oxidative stress induced-neurodegenerative disease: the need for antioxidants that penetrate the blood brain barrier. Neuropharmacology 40, 959–975.
Gortelmeyer R. and Erbler H. (1992) Memantine in the treatment of mild to moderate dementia syndrome. Drug Res. 42, 904–913.
Greenamyre E. F., Maragos R. L., Albin J. B., et al. (1988) Glutamate transmission and toxicity in Alzheimer’s disease. Prog. Neuropsychopharmacol. Biol. Psychiatry 12, 421–430.
Grundman M. (2000) Vitamin E and Alzheimer’s disease: the basis for additional clinical trials. Am. J. Clin. Nutr. 71, 630S-636S.
Harman D. (1992) Role of free radicals in aging and disease. Ann. N. Y. Acad. Sci. 673, 126–134.
Hensley K., Hall N., Subramanian R., et al. (1995) Brain regional correspondence between Alzheimer disease histopathology and biomarkers of protein oxidation. J. Neurochem. 65, 2146–2156.
Hoyer S. (1996) Oxidative metabolism deficiencies in brains of patients with Alzheimer’s disease. Acta Neurol. Scand. 93, 18–24.
Knopman D. (2001) Pharmacotherapy for Alzheimer disease. Curr. Neurol. Neurosci. Rep. 1, 428–434.
Laurin D., Foley D. J., Masaki K. H., et al. (2002) Vitamin E and C supplements and risk of dementia. JAMA 288, 2266–2268.
Lovell M. A. and Markesbery W. R. D. (2001) Ration of 8-hydroxyguanine in intact DNA to free 8-hydroxyguanine is increased in Alzheimer’s disease ventricular cerebrospinal fluid. Arch. Neurol. 58, 392–396.
Maccioni R. B., Munoz J. P., and Barbeito L. (2001) The molecular bases of Alzheimer’s disease and other neurodegenerative disorders. Arch. Med. Res. 32, 367–381.
Marcus D. L., Thomas C., Rodriguez C., et al. (1998) Increased peroxidation and reduced antioxidant enzyme activity in Alzheimer disease. Exp. Neurol. 150, 40–44.
Masaki K. H., Losonczy K. G., Izmirlian G., et al. (2000) Association of vitamin E and C supplement use with cognitive function and dementia in elderly men. Neurology 54, 1265–1272.
Mattson M. P., Cheng B., Davis D., et al. (1992) β-Amyloid peptides destabilize calcium homeostasis and render human cultured neurons vulnerable to excitotoxicity. J. Neurosci. 12, pp. 376–389.
Mattson M. P., Barger S. W., Lieberburg I., et al. (1993) β-Amyloid precursor protein metabolites and loss of neuronal Ca2+ homeostasis in Alzheimer’s disease. Trends Neurosci. 16, 409–414.
Matsuoka Y., Picciano M., La Francois J., et al. (2001) Fibrillar β-amyloid evokes oxidative damage in transgenic mouse model of Alzheimer’s disease. Neuroscience 104, 609–613.
Mecocci P., MacGarvey U., and Beal M. F. (1994) Oxidative damage to mitochondrial DNA is increased in Alzheimer disease. Ann. Neurol. 36, 747–751.
Montine T. J., Markesbery W. R., Morrow J. D., et al. (1998) Cerebrospinal fluid F2-isoprostane levels are increased in Alzheimer disease. Ann. Neurol. 44, 410–413.
Morris M. C., Beckett L. A., Scherr P. A., et al. (1998) Vitamin E and vitamin C supplement use and risk of incident Alzheimer disease. Alzheimer Dis. Assoc. Disord. 12, 121–126.
Morris M. C., Evans D. A., Bienias J. L., et al. (2002) Dietary intake of antioxidants nutrients and risk of incident Alzheimer disease in a biracial community study. JAMA 287, 3230–3237.
Nunomura A., Perry G., Aliev G., et al. (2001) Oxidative damage is the earliest event in Alzheimer disease. J. Neuropathol. Exp. Neurol. 60, 759–767.
Palmer A. M. and Burns M. A. (1994) Selective increase in lipid peroxidation in the inferior temporal cortex in Alzheimer’s disease. Brain Res. 645, 338–342.
Pappolla M.A., Omar R.A., Kim K.S., et al. (1992) Immunohistochemical evidence of antioxidant stress in Alzheimer’s disease. Am. J. Pathol. 140, 621–628.
Penney J. B., Maragos W. F., Greenamyre J. T., et al. (1990) Excitatory amino acid binding sites in the hippocampal region of Alzheimer’s disease and other dementias. J. Neurol. Neurosurg. Psychiatry 53, 314–320.
Pitchumoni S. S. and Doraiswamy P. M. (1998) Current status of antioxidant therapy for Alzheimer’s disease. J. Am. Geriatr. Soc. 46, 1566–1572.
Pratico D. (2002) Alzheimer’s disease and oxygen radicals: new insights. Biochem. Pharmacol. 63, 563–567.
Pratico D., Clark C. M., Liun F., et al. (2002) Increase of brain oxidative stress in mild cognitive impairment a possible predictor of Alzheimer’s disease. Arch. Neurol. 59, 972–976.
Pratico D., Uryu K., Leight S., et al. (2001) Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer’s amyloidosis. J. Neurosci. 21, 4183–4187.
Reisberg B. (2000) Memantine in moderately severe to severe Alzheimer’s disease (AD): results of a placebocontrolled 6-month trial. Neurobiol. Ageing 21, S275.
Ramassamy C., Krzywokowski P., Bastianetto S., et al., (1998) Apolipoprotein E, oxidative stress and EGb 761 in Alzheimer’s disease brain, in Gingo Biloba Extract (EGb 761) Study: Lesson from Cell Biology, Packer L. and Christen Y., eds., Elsevier, Paris, pp. 69–83.
Rosler M., Retz W., Thome J., et al. (1998) Free radicals in Alzheimer’s dementia: currently available therapeutic strategies. J. Neural Transm. Suppl. 54, 211–219.
Rutten B. P., Steinbusch H. W., Korr H., and Schmitz C. (2002) Antioxidants and Alzheimer’s disease: from bench to bedside (and back again). Curr. Opin. Clin. Nutr. Metab. Care 5, 645–651.
Sano M., Ernesto C., Thomas R.G., et al. (1997) A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease; the Alzheimer’s disease Cooperative Study. N. Engl. J. Med. 336, 1216–1222.
Selkoe D. J. (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol. Rev. 81, 741–766.
Smith M. A., Kutty R. K., Richey P. L., et al. (1994) Heme oxygenase-1 is associated with the neurofibrillary pathology of Alzheimer’s disease. Am. J. Pathol. 140, 621–628.
Sun Y. X., Crisby M., Lindgren S., et al. (2003) Pravastatin inhibits pro-inflammatory effects of Alzheimer’s peptide Abeta(1–42) in glioma cell culture in vitro. Pharmacol. Res. 47, 119–126.
Tabet N., Birks J., and Evans G. (2000) Vitamin E for Alzheimer’s disease. Cochrane Databases Syst. Rev. 4.
Wisniewski T. and Sigurdsson E. M. (2002) Immunization treatment approaches in Alzheimer and prion diseases. Curr. Neurol. Neurosci. Rep. 2, 400–404.
Yan S. D., Chen X., Schmidt A. M., et al. (1994) Glycated tau protein in Alzheimer’s disease: a mechanism for induction of oxidant stress. Proc. Natl. Acad. Sci. U. S. A. 91, 7787–7791.
Zemlan F. P., Theinhaus O. J., and Bosmann H. B. (1989) Supperoxide dismutase activity in Alzheimer’s disease: possible mechanism for paired helical formation. Brain Res. 476, 160–162.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Gilgun-Sherki, Y., Melamed, E. & Offen, D. Antioxidant treatment in alzheimer’s disease. J Mol Neurosci 21, 1–11 (2003). https://doi.org/10.1385/JMN:21:1:1
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1385/JMN:21:1:1