Advertisement

Oxidative stress in Alzheimer’s Disease: Implications for Prevention and Therapy

  • Christian Behl
Part of the Subcellular Biochemistry book series (SCBI, volume 38)

Abstract

Oxidative stress is a marker of neurodegeneration and has been recently shown to be also involved in the early stages of the pathogenesis of various neurodegenerative disorders. In general, all biomolecules of the cell can be oxidized and thereby damaged. Consequently, the concept of neuroprotection by antioxidants has been developed. In many cases the direct scavanging of free radicals have been used as a strategy to prevent oxidative stress damage and a variety of physiological and synthetic antioxidant molecules have been identified and synthesized including the female sex homone estrogen. In Alzheimer’s Disease amyloid-β protein on its way to brain deposition can also induce oxidative changes rendering nerve cells more vulnerable to additional insults. In addition, inflammatory mediators are attracted by amyloid deposits that can further speed up the generation of an oxidative micro-environment. Based on recent clinical data the use of a combination of various antioxidants might indeed be effective in preventing Alzheimer’s Disease. Nevertheless, the exact molecular mechanisms and the real impact of oxidative stress on the development and progression of Alzheimer’s Disease as well as of other neurodegenerative disorders still needs to be further investigated.

Key words

Oxidative stress free radicals lipid peroxidation protein oxidation DNA oxidation amyloid-β protein inflammation vitamin E vitamin C anti-inflammatory drugs estrogen blood-brain-barrier 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Akiyama, H., Barger, S., Barnum, S., Bradt, B., Bauer, J., Cole, G.M., Cooper, N.R., Eikelenboom, P., Emmerling, M., Fiebich, B.L., Finch, C.E., Frautschy, S., Griffin, W.S., Hampel, H., Hull, M., Landreth, G., Lue, L., Mrak, R., Mackenzie, I.R., McGeer, P.L., O’Banion, M.K., Pachter, J., Pasinetti, G., Plata-Salaman, C., Rogers, J., Rydel, R., Shen, Y., Streit, W., Strohmeyer, R., Tooyoma, I., Van Muiswinkel, F.L., Veerhuis, R., Walker, D., Webster, S., Wegrzyniak, B., Wenk, G., and Wyss-Coray, T., 2000, Inflammation and Alzheimer’s disease. Neurobiol. Aging. 21: 383–421.PubMedCrossRefGoogle Scholar
  2. Ames, B.N, Shigenda, M.K, and Hagen, T.M., 1993, Oxidants, antioxidants, and the degenerative diseases of aging. Proc Nad Acad Sci USA 90: 7915–7922.CrossRefGoogle Scholar
  3. Babior, B.M., 2000, Phagocytes and oxidative stress. Am. J. Med. 109: 33–44.PubMedCrossRefGoogle Scholar
  4. Behl, C., 2002, Oestrogen as a neuroprotective hormone. Nat. Rev. Neuro Sci. 3: 433–442.Google Scholar
  5. Behl, C., Davis, J., Cole, G.M., and Schubert, D., 1992, Vitamin E protects nerve cells from amyloid beta protein toxicity. Biochem. Biophys. Res. Commun. 186: 944–950.PubMedCrossRefGoogle Scholar
  6. Behl, C., Davis, J.B., Lesley R., and Schubert, D.,. 1994, Hydrogen peroxide mediates amyloid beta protein atomicity. Cell 77: 817–827.PubMedCrossRefGoogle Scholar
  7. Breitner, J.C., and Zandi, P.P., 2001, Do nonsteroidal antiinflammatory drugs reduce the risk of Alzheimer’s disease? N. Engl. J. Med. 345: 1567–1568.PubMedCrossRefGoogle Scholar
  8. Brusco, L.I., Marquez, M., and Cardinali, D.P., 2000, Melatonin treatment stabilizes chronobiologic and cognitive symptoms in Alzheimer’s disease. Neuroendocrinol. Lett. 21: 39–42.PubMedGoogle Scholar
  9. Carlson, M.C., Zandi, P.P., Plassman, B.L., Tschanz, J.T., Welsh-Bohmer, K.A., Steffens, D.C., Bastian, L.A., Mehta, K.M., and Breitner, J.C., 2001, Cache County Study Group. Hormone replacement therapy and reduced cognitive decline in older women: the Cache County Study. Neurology 57: 2210–2216.PubMedGoogle Scholar
  10. Christen, Y., 2000, Oxidative stress and Alzheimer disease. Am. J. Clin. Nutr. 71: 621S–629S.PubMedGoogle Scholar
  11. Crapper McLachlan, D.R., Dalton, A.J., Kruck, T.P., Bell, M.Y., Smith, W.L., Kalow, W., Andrews, D.F., 1991, Intramuscular desferrioxamine in patients with Alzheimer’s disease. Lancet 337: 1304–1308.PubMedCrossRefGoogle Scholar
  12. Dewachter, I., van Dorpe, J., Spittaels, K., Tesseur, I., Van Den Haute, C., Moechars, D., Van Leuven, F., 2000, Modeling Alzheimer’s disease in transgenic mice: effect of age and of presenilinl on amyloid biochemistry and pathology in APP/London mice. Exp. Gerontol. 35: 831–841.PubMedCrossRefGoogle Scholar
  13. Floyd, R.A., 1999, Antioxidants, oxidative stress, and degenerative neurological disorders. Proc. Soc. Exper. Biol. Med. 222: 236–245.CrossRefGoogle Scholar
  14. Galeazzi, L., Ronchi, P., Franceschi, C., and Giunta, S., 1999, In vitro peroxidase oxidation induces stable dimers of beta-amyloid (1-42) through dityrosine bridge formation. Amyloid 6: 7–13.PubMedGoogle Scholar
  15. Games, D., Adams, D., Alessandrini, R., Barbour, R., Berthelette, P., Blackwell, C., Carr, T., Clemens, J., Donaldson, T., Gillespie, F, et al., 1995, Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 373: 523–527.PubMedCrossRefGoogle Scholar
  16. Gouras, G.K., and Beal, M.F., 2001, Metal chelator decreases Alzheimer beta-amyloid plaques. Neuron 30: 641–642.PubMedCrossRefGoogle Scholar
  17. Grundman, M.. 2000, Vitamin E and Alzheimer disease: the basis for additional clinical trials. Am. J. Clin. Nutr. 71: 630S–636S.PubMedGoogle Scholar
  18. Gutzmann, H., and Hadler, D., 1998, Sustained efficacy and safety of idebenone in the treatment of Alzheimer’s disease: update on a 2-year double-blind multicentre study. J. Neural. Transm. Suppl. 54: 301–310.Google Scholar
  19. Halliwell, B., and Gutteridge, J.M.C., 2003, Free Radicals in Biology and Medicine. Oxford University Press.Google Scholar
  20. Harman D., 1992, Free radical theory of aging. Mutan Res. 275: 257–266.Google Scholar
  21. Harman D., 1996, A hypothesis on pathogenesis of Alzheimer’s disease. Ann. NY Acad. Sci. 786: 152–168.PubMedGoogle Scholar
  22. Holcomb, L., Gordon, M.N., McGowan, E., Yu, X., Benkovic, S., Jantzen, P., Wright, K., Saad, I., Mueller, R., Morgan, D., Sanders, S., Zehr, C., O’Campo, K., Hardy, J., Prada, C.M., Eckman, C., Younkin, S., Hsiao, K., and Duff, K., 1998, Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nature Med. 1: 97–100.Google Scholar
  23. Huang, X., Cuajungco, M.P., Atwood, C.S., Hartshorn, M.A., Tyndall, J.D., Hanson, G.R., Stokes, K.C., Leopold, M., Multhaup, G., Goldstein, L.E., Scarpa, R.C., Saunders, A.J., Lim, J., Moir, R.D., Glabe, C., Bowden, E.F., Masters, C.L., Fairlie, D.P., Tanzi, R.E., and Bush, A.I., 1999, Cu(II) potentiation of alzheimer abeta neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J. Biol. Chem. 274: 37111–37116.PubMedCrossRefGoogle Scholar
  24. in t’ Veld, B..A., Ruitenberg, A., Hofman, A., Launer, L.J., van Duijn, C.M., Stijnen, T., Breteler, M.M., and Stricker, B.H. 2001, Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N. Engl. J. Med. 345: 1515–1521.CrossRefGoogle Scholar
  25. Joseph, J, Skuitt-Hale, B, Denisova, N.A, Martin, A, Perry, G, and Smith, M.A, 2001, Copernicus revisited: amyloid β in Alzheimer’s disease. Neurobiol.. Aging 22: 131–146.PubMedCrossRefGoogle Scholar
  26. Klotz, L.O., Sies, H., 2003, Defenses against peroxynitrite: selenocompounds and flavonoids. Toxicol Lett. 140–141: 125–132.PubMedCrossRefGoogle Scholar
  27. Koppaka, V., and Axelsen, P.H., 2000, Accelerated accumulation of amyloid beta proteins on oxidatively damaged lipid membranes. Biochemistry 39: 10011–10016.PubMedCrossRefGoogle Scholar
  28. Markesberry, W.R., and Carney, J.M., 1999, Oxidative alterations in Alzheimer’s disease. Brain Pathol. 9: 133–146.CrossRefGoogle Scholar
  29. McGeer, P.L., and, McGeer, E.G., 1996, Anti-inflammatory drugs in the fight against Alzheimer’s disease. Ann. N. Y. Acad. Sci. 777: 213–220.PubMedGoogle Scholar
  30. McGeer, P.L., and Rogers, J., 1992, Anti-inflammatory agents as a therapeutic approach to Alzheimer’s disease. Neurology 42: 447–449.PubMedGoogle Scholar
  31. Moosmann, B., and Behl, C., 1999, The antioxidant neuroprotective effects of estrogens and phenolic compounds are independent from their estrogenic properties. Proc. Natl. Acad. Sci. USA 96: 8867–8872.PubMedCrossRefGoogle Scholar
  32. Moosmann, B., and Behl, C., 2002, Antioxidants as treatment for neurodegenerative disorders. Expert Opin. Investig. Drugs. 11: 1407–1435.PubMedCrossRefGoogle Scholar
  33. Nunomura, A., Perry, G., Pappolla, M.A., Friedland, R.P., Hirai, K., Chiba, S., and Smith M.A., 2000, Neuronal oxidative stress precedes amyloid-beta deposition in Down syndrome. J. Neuropathol. Ex.p Neurol. 59: 1011–1017.Google Scholar
  34. Nunomura, A., Perry, G., Aliev, G., et al., 2001, Cytosolic peroxidative damage is an early event in Alzheimer’s disease. J. Neuropathol. Exp. Neurol. 60: 759–767.PubMedGoogle Scholar
  35. Nourhashemi, F., Gillette-Guyonnet, S., Andrieu, S., Ghisolfi, A., Ousset, P.J., Grandjean, H., Grand, A., Pous, J., Vellas, B., and Albarede, J.L., 2000, Alzheimer disease: protective factors. Am. J. Clin. Nutr. 71: 643S–649S.PubMedGoogle Scholar
  36. Oken, B.S., Storzbach, D.M., and Kaye, J.A., 1998, The efficacy of Ginkgo biloba on cognitive function in Alzheimer disease. Arch. Neurol. 55: 1409–1415.PubMedCrossRefGoogle Scholar
  37. Paganini-Hill, A., and Henderson, V.W., 1996, Estrogen replacement therapy and risk of Alzheimer disease. Arch Intern Med. 156: 2213–2217.PubMedCrossRefGoogle Scholar
  38. Perutz, M.F., and Windle, A.H., 2001, Cause of neural death in neurodegenerative diseases attributable to expansion of glutamine repeats. Nature 412: 143–144.PubMedCrossRefGoogle Scholar
  39. Pratico, D., and Delanty, N., 2000, Oxidative injury in diseases of the central nervous system: focus on Alzheimer’s disease. Am. J. Med. 109: 577–585.PubMedCrossRefGoogle Scholar
  40. Pratico, D, Uryu, K, Leight, S., Trojanoswki, J.Q., and Lee, V.M., 2001, Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J. Neuro Sci. 21: 4183–4187.Google Scholar
  41. Sano, M., Ernesto, C., Thomas, R.G., Klauber, M.R., Schafer, K., Grundman, M., Woodbury, P., Growdon, X, Cotman, C.W., Pfeiffer, E., Schneider, L.S., and Thal, L.J., 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.PubMedCrossRefGoogle Scholar
  42. Selkoe, D.J., 1999, Translating cell biology into therapeutic advances in Alzheimer’s disease. Nature 399 (Supp I) A23–31.PubMedCrossRefGoogle Scholar
  43. Sies, H., 1993, Strategies of antioxidant defense. Eur. J. Bio Chem. 215: 213–219.Google Scholar
  44. Smith, M.A., Harris, P.L., Sayre, L.M., and Perry, G., 1997, Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc. Nat.l Acad. Sci. USA. 1997 94: 9866–9868.CrossRefGoogle Scholar
  45. Spagnoli, A., Lucca, U., Menasce, G., Bandera, L., Cizza, G., Forloni, G., Tettamanti, M., Frattura, L., Tiraboschi, P., Comelli, M., et al., 1991, Long-term acetyl-L-carnitine treatment in Alzheimer’s disease. Neurology 41: 1726–1732.PubMedGoogle Scholar
  46. Sturchler-Pierrat, C., Abramowski, D., Duke, M., Wiederhold, K.H., Mistl, C., Rothacher, S., Ledermann, B., Burki, K., Frey, P., Paganetti, P.A., Waridel, C., Calhoun, M.E., Jucker, M., Probst, A., Staufenbiel, M., and Sommer, B., 1997, Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc. Natl. Acad. Sci. USA 94: 13287–13292.PubMedCrossRefGoogle Scholar
  47. Tang, M.X., Jacobs, D., Stern, Y., Marder, K., Schofield, P., Gurland, B., Andrews, H., and Mayeux, R., 1996, Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease. Lancet 348: 429–432.PubMedCrossRefGoogle Scholar
  48. Thal, L.J., Calvani, M., Amato, A., and Carta, A., 2000, A 1-year controlled trial of acetyl-1-carnitine in early-onset AD. Neurology 55: 805–810.PubMedGoogle Scholar
  49. Thal, L.J., Carta, A., Clarke, W.R., Ferris, S.H., Friedland, R.P., Petersen, R.C., Pettegrew, J.W., Pfeiffer, E., Raskind, M.A., Sano, M., Tuszynski, M.H., and Woolson, R.F., 1996, A 1-year multicenter placebo-controlled study of acetyl-L-carnitine in patients with Alzheimer’s disease. Neurology 47: 705–711.PubMedGoogle Scholar
  50. Walsh, D.M., Klyubin, I., Fadeeva, J.V., Cullen, W.K., Anwyl, R., Wolfe, M.S., Rowan, M.J., and Selkoe, D.J., 2002, Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416: 535–539.PubMedCrossRefGoogle Scholar
  51. Waring, S.C., Rocca, W.A., Petersen, R.C., O’Brien, P.C., Tangalos, E.G., and Kokmen, E., 1999, Postmenopausal estrogen replacement therapy and risk of AD: a population-based study. Neurology 52: 965–970.PubMedGoogle Scholar
  52. Weggen, S., Eriksen, J.L., Das, P., Sagi, S.A., Wang, R., Pietrzik, C.U., Findlay, K.A., Smith, T.E., Murphy, M.P., Bulter, T., Kang, D.E., Marquez-Sterling, N., Golde, T.E., and Koo, E.H., 2001, A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 414: 212–216.PubMedCrossRefGoogle Scholar
  53. Yankner, B.A., Dawes, L.R., Fisher, S., Villa-Komaroff, L., Oster-Granite, M.L., and Neve, R.L., 1989, Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer’s disease. Science 245: 417–420.PubMedCrossRefGoogle Scholar
  54. Zandi, P.P., Anthony, J.C., Khachaturian, A.S., Stone, S.V., Gustafson, D., Tschanz, J.T., Norton, M.C., Welsh-Bohmer, K.A., and Breitner, J.C., 2004, Cache County Study Group. Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study. Arch. Neurol. 61: 82–88.PubMedCrossRefGoogle Scholar
  55. Zandi, P.P., and Breitner, J.C., 2001, Do NSAIDs prevent Alzheimer’s disease? And, if so, why? The epidemiological evidence. Neurobiol Aging 22: 811–817.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2005

Authors and Affiliations

  • Christian Behl
    • 1
  1. 1.Institute for Physiological Chemistry & Pathobiochemistry, Faculty of MedicineJohannes Gutenberg University, MainzMainzGermany

Personalised recommendations