Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Apolipoprotein E allele–specific antioxidant activity and effects on cytotoxicity by oxidative insults and β–amyloid peptides

Abstract

The apolipoprotein E (APOE) E4 allele is associated with Alzheimer's disease, cardiovascular disease, and decreased longevity. To probe the mechanism of these associations, cell lines were created which secrete each apoE isoform. ApoE conditioned media, purified apoE, and commercially obtained apoE protected B12 cells from hydrogen peroxide cytotoxicity with E2 > E3 > E4. Physiological levels of apoE protected cells from β–amyloid peptides, while higher doses of apoE led to increased cytotoxicity. E2 > E3 > E4 possessed antioxidant activity, and apoE bound certain metal ions. The decreased antioxidant activity of E4 could contribute to its association with Alzheimer's disease, cardiovascular disease and decreased longevity.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Corder, E.H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921–923 (1993).

    Article  CAS  Google Scholar 

  2. Mayeux, R. et al. The apolipoprotein epsilon 4 allele in patients with Alzheimer's disease. Ann. Neurol. 34, 752–754 (1993).

    Article  CAS  Google Scholar 

  3. van Duijin, C.M. et al. Apolipoprotein E4 allele in a population-based study of early-onset Alzheimer's disease. Nature Genetics 7, 74–78 (1994).

    Article  Google Scholar 

  4. Hendrie, H.C. et al. Apolipoprotein E genotypes and AD in a community study of elderly African Americans. Ann. Neurol. 37, 118–120 (1995).

    Article  CAS  Google Scholar 

  5. Saunders, A.M. et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology 43, 1467–1472 (1993).

    Article  CAS  Google Scholar 

  6. Corder, E.H. et al. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nature Genet. 7, 180–184 (1994).

    Article  CAS  Google Scholar 

  7. Maestre, G. et al. Apolipoprotein E and Alzheimer’s disease: ethnic variation in genotypic risks. Ann. Neurol. 37, 254–259 (1995).

    Article  CAS  Google Scholar 

  8. Xhignesse, M., Lussier-Cacan, S., Sing, C.F., Kessling, A.M. & Davignon, J. Influences of common variants of apolipoprotein E on measures of lipid metabolism in a sample selected for health. Arterioscler. Thromb. 11, 1100–1110 (1991).

    Article  CAS  Google Scholar 

  9. Stengard, J.H. et al. Apolipoprotein E polymorphism predicts death from coronary heart disease in a longitudinal study of elderly Finnish men. Circulation 91, 265–269 (1995).

    Article  CAS  Google Scholar 

  10. van Bockxmeer, F.M., Mamotte, C.D., Gibbons, F.R. & Taylor, R.R. Apolipoprotein epsilon 4 homozygosity — a determinant of restenosis after coronary angioplasty. Atheroscler. 110, 195–202 (1994).

    Article  CAS  Google Scholar 

  11. Schachter, F. et al. Genetic associations with human longevity at the apoE and ACE loci. Nature Genet. 6, 29–32 (1994).

    Article  CAS  Google Scholar 

  12. Louhija, J. et al. Aging and genetic variation of plasma apolipoproteins. Arterioscler. Thromb. 14, 1084–1089 (1994).

    Article  CAS  Google Scholar 

  13. Goate, A. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349, 704–706 (1991).

    Article  CAS  Google Scholar 

  14. Pike, C.J., Burdick, D., Walencewicz, A.J., Gabe, C.G. & Cotman, C.W. Neurodegeneration induced by β-amyloid peptides in vitro: the role of peptide assembly state. J. Neurosci. 13, 1676–1687 (1993).

    Article  CAS  Google Scholar 

  15. Behl, C., Davis, J., Cole, G.M. & Schubert, D. Vitamin E protects nerve cells from amyloid βprotein toxicity. Biochem. Biophys. Res. Comm. 186, 944–950 (1992).

    Article  CAS  Google Scholar 

  16. Behl, C., Davis, J., Lesley, R. & Schubert, D. Hydrogen peroxide mediates amyloid βprotein toxicity. Cell 77, 817–827 (1994).

    Article  CAS  Google Scholar 

  17. Butterfield, D.A., Hensley, K., Harris, M., Mattson, M. & Carney, J. β-amyloid peptide free radical fragments initiate synaptosomal lipoperoxidation in a sequence specific fashion: implications to Alzheimer's disease. Biochem. Biophys. Res. Comm. 200, 710–715 (1994).

    Article  CAS  Google Scholar 

  18. Wisniewski, T. & Frangione, B. Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid. Neurosci. Lett 135, 235–238 (1992).

    Article  CAS  Google Scholar 

  19. Sanan, D.A. et al. Apolipoprotein E associates with β amyloid peptide of Alzheimer's disease to form novel monofibrils. J. Clin. Invest. 94, 860–869 (1994).

    Article  CAS  Google Scholar 

  20. Ma, J., Yee, A., Brewer, H.B., Das, S. & Potter, H. Amyloid-associated proteins α1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer β-protein into filaments. Nature 372, 92–94 (1994).

    Article  CAS  Google Scholar 

  21. Nathan, B.P. et al. Differential effects of apolipoprotein E3 and E4 on neuronal growth in vitro. Science 264, 850–852 (1994).

    Article  CAS  Google Scholar 

  22. Hartmann, H., Eckert, A. & Muller, W.E. Apolipoprotein E and cholesterol affect neuronal calcium signaling: the possible relationship between β-amyloid and neurotoxicity. Biochem. Biophys. Res. Comm. 200, 1185–1192 (1994).

    Article  CAS  Google Scholar 

  23. Strittmater, W.J. et al. Isoform-specific interactions of apolipoprotein E with microtubule associated protein tau: Implications for Alzheimer disease. Proc. Natl. Acad Sci. U. S. A. 91, 11183–11186 (1994).

    Article  Google Scholar 

  24. Hayek, T., Oikinine, J., Brook, J.G. & Avriam, M. Increased plasma and lipoprotein lipid peroxidation in apolipoprotein E deficient mice. Biochem Biophys. Res. Comm. 201, 1567–1574 (1994).

    Article  CAS  Google Scholar 

  25. Rinninger, F. & Pittman, R.C. Mechanism of the cholesteryl ester transfer protein-mediated uptake of high density lipoprotein cholesteryl esters by Hep G2 cells. J. Biol. Chem. 264, 6111–6118 (1989).

    CAS  PubMed  Google Scholar 

  26. Jaeckle, S., Brady, S.E. & Havel, R.J. Membrane binding sites for plasma lipoproteins on endosomes from rat liver. Proc. Natl. Acad. Sci. U.S.A. 86, 1880–1884 (1989).

    Article  CAS  Google Scholar 

  27. Weisgraber, K.H., Innerarity, T.L. & Mahley, R.W. Role of lysine residues of plasma lipoproteins in high affinity binding to cell surface receptors on human fibroblasts. J. Biol. Chem. 253, 9053–9062 (1978).

    CAS  PubMed  Google Scholar 

  28. Maxwell, S.J.R., Wiklund, O. & Bondjers, G. Measurement of antioxidant activity in lipoproteins using enhanced chemiluminescence. Atheroscler. 111, 79–89 (1994).

    Article  CAS  Google Scholar 

  29. Dong, L.M. et al. Human apolipoprotein E. Role of arginine 61 in mediating the lipoprotein preferences of the E3 and E4 isoforms. J. Biol. Chem. 269, 22358–22365 (1994).

    CAS  PubMed  Google Scholar 

  30. Schaefer, E.J. et al. Familial apolipoprotein E deficiency. J. Clin. Invest. 78, 1206–1219 (1986).

    Article  CAS  Google Scholar 

  31. Plump, A.S. et al. Severe hypercholesterolaemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell 71, 343–353 (1992).

    Article  CAS  Google Scholar 

  32. Lehtimaki, T. et al. Apolipoprotein E polymorphism and its influence on apoE concentrations in cerebrospinal fluid in Finnish patients with Alzheimer's disease. Hum. Genet. 95, 39–42 (1995).

    Article  CAS  Google Scholar 

  33. Burdick, D. et al. Assembly and aggregation properties of synthetic Alzheimer's A/4β amyloid peptide analogs. J. Biol. Chem. 267, 546–554 (1992).

    CAS  PubMed  Google Scholar 

  34. Strittmatter, W.J. et al. Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc. Natl. Acad. Sci. U.S.A. 90, 8098–8102 (1993).

    Article  CAS  Google Scholar 

  35. Wisniewski, T., Golabek, A., Matsubara, E., Ghiso, J. & Frangione, B. Apolipoprotein E: binding to soluble Alzheimer's beta-amyloid. Biochem. Biophys. Res. Comm. 192, 359–365 (1993).

    Article  CAS  Google Scholar 

  36. Evans, K.C., Berger, E.P., Cho, C.-G., Weisgraber, K.H. & Lansbury, P.T.J. Apolipoprotein E is a kinetic but not a thermodynamic inhibitor of amyloid formation: Implications for the pathogenesis and treatment of Alzheimer disease. Proc. Natl. Acad. Sci. U.S.A. 92, 763–767 (1995).

    Article  CAS  Google Scholar 

  37. LaDu, M.J. et al. Isoform-specific binding of apolipoprotein E to β-amyloid. J. Biol. Chem. 269, 23403–23406 (1994).

    CAS  PubMed  Google Scholar 

  38. LaDu, M.J. et al. Purification of apoE attenuates isoform-specific binding to β-amyloid. J. Biol. Chem. 270, 9039–9042 (1995).

    Article  CAS  Google Scholar 

  39. Whitson, J.S. et al. Attenuation of the neurotoxic effect of β amyloid by apolipoprotein E. Biochem. Biophys. Res. Comm. 199, 163–170 (1994).

    Article  CAS  Google Scholar 

  40. Buettner, G.R. The pecking order of free radicals and antioxidants: lipid peroxidation, alpha-tocopherol, and ascorbate. Arch. Biochem. Biophys. 300, 535–543 (1993).

    Article  CAS  Google Scholar 

  41. Kunitake, S.T., Jarvis, M.R., Hamilton, R.L. & Kane, J.P. Binding of transition metals by apolipoprotein A-l-containing plasma lipoproteins: inhibition of oxidation of low density lipoproteins. Proc. Natl. Acad. Sci. U.S.A. 89, 6993–6997 (1992).

    Article  CAS  Google Scholar 

  42. Ehrenwald, E., Chisolm, G.M. & Fox, P.L. Intact human ceruloplasmin oxidatively modifies low density lipoprotein. J. Clin. Invest. 93, 1493–1501 (1994).

    Article  CAS  Google Scholar 

  43. Mantyh, P.W. et al. Aluminum, iron, and zinc ions promote aggregation of physiological concentrations of beta-amyloid peptide. J. Neurochem. 61, 1171–1174 (1993).

    Article  CAS  Google Scholar 

  44. Regan, L. Protein design: novel metal-binding sites. Trends Biochem. Sci. 20, 280–285 (1995).

    Article  CAS  Google Scholar 

  45. Smith, J.D., Melian, A., Leff, T. & Breslow, J.L. Expression of the human apolipoprotein E gene is regulated by multiple positive and negative elements. J. Biol. Chem. 263, 8300–8308 (1988).

    CAS  PubMed  Google Scholar 

  46. Buege, J.A. & Aust, S.D. Microsomal lipid peroxidation. Meth. Enzymol. 52, 302–310 (1978).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Miyata, M., Smith, J. Apolipoprotein E allele–specific antioxidant activity and effects on cytotoxicity by oxidative insults and β–amyloid peptides. Nat Genet 14, 55–61 (1996). https://doi.org/10.1038/ng0996-55

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0996-55

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing