Skip to main content
PMC home page
Biochemical Journal logoLink to Biochemical Journal
. 2000 Jul 1;349(Pt 1):77–84. doi: 10.1042/0264-6021:3490077

Apolipoprotein E includes a binding site which is recognized by several amyloidogenic polypeptides.

M H Baumann 1, J Kallijärvi 1, H Lankinen 1, C Soto 1, M Haltia 1
PMCID: PMC1221122  PMID: 10861213

Abstract

Inheritance of the apolipoprotein E (apoE) epsilon 4 allele is a risk factor for late-onset Alzheimer's disease (AD). Biochemically apoE is present in AD plaques and neurofibrillary tangles of the AD brain. There is a high avidity and specific binding of apoE and the amyloid beta-peptide (A beta). In addition to AD apoE is also present in many other cerebral and systemic amyloidoses, Down's syndrome and prion diseases but the pathophysiological basis for its presence is still unknown. In the present study we have compared the interaction of apoE with A beta, the gelsolin-derived amyloid fragment AGel(183-210) and the amyloidogenic prion fragments PrP(109-122) and PrP(109-141). We show that, similar to A beta, also AGel and PrP fragments can form a complex with apoE, and that the interaction between apoE and the amyloidogenic protein fragments is mediated through the same binding site on apoE. We also show that apoE increases the thioflavin-T fluorescence of PrP and AGel and that apoE influences the content of beta-sheet conformation of these amyloidogenic fragments. Our results indicate that amyloids and amyloidogenic prion fragments share a similar structural motif, which is recognized by apoE, possibly through a single binding site, and that this motif is also responsible for the amyloidogenicity of these fragments.

Full Text

The Full Text of this article is available as a PDF (199.1 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arai H., Muramatsu T., Higuchi S., Sasaki H., Trojanowski J. Q. Apolipoprotein E gene in Parkinson's disease with or without dementia. Lancet. 1994 Sep 24;344(8926):889–889. doi: 10.1016/s0140-6736(94)92862-2. [DOI] [PubMed] [Google Scholar]
  2. Bales K. R., Verina T., Dodel R. C., Du Y., Altstiel L., Bender M., Hyslop P., Johnstone E. M., Little S. P., Cummins D. J. Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat Genet. 1997 Nov;17(3):263–264. doi: 10.1038/ng1197-263. [DOI] [PubMed] [Google Scholar]
  3. Baumann M. H., Wisniewski T., Levy E., Plant G. T., Ghiso J. C-terminal fragments of alpha- and beta-tubulin form amyloid fibrils in vitro and associate with amyloid deposits of familial cerebral amyloid angiopathy, British type. Biochem Biophys Res Commun. 1996 Feb 6;219(1):238–242. doi: 10.1006/bbrc.1996.0211. [DOI] [PubMed] [Google Scholar]
  4. Benjamin R., Leake A., Edwardson J. A., McKeith I. G., Ince P. G., Perry R. H., Morris C. M. Apolipoprotein E genes in Lewy body and Parkinson's disease. Lancet. 1994 Jun 18;343(8912):1565–1565. doi: 10.1016/s0140-6736(94)92961-0. [DOI] [PubMed] [Google Scholar]
  5. Castano E. M., Prelli F., Wisniewski T., Golabek A., Kumar R. A., Soto C., Frangione B. Fibrillogenesis in Alzheimer's disease of amyloid beta peptides and apolipoprotein E. Biochem J. 1995 Mar 1;306(Pt 2):599–604. doi: 10.1042/bj3060599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chargé S. B., Esiri M. M., Bethune C. A., Hansen B. C., Clark A. Apolipoprotein E is associated with islet amyloid and other amyloidoses: implications for Alzheimer's disease. J Pathol. 1996 Aug;179(4):443–447. doi: 10.1002/(SICI)1096-9896(199608)179:4<443::AID-PATH612>3.0.CO;2-7. [DOI] [PubMed] [Google Scholar]
  7. Chartier-Harlin M. C., Parfitt M., Legrain S., Pérez-Tur J., Brousseau T., Evans A., Berr C., Vidal O., Roques P., Gourlet V. Apolipoprotein E, epsilon 4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimer's disease: analysis of the 19q13.2 chromosomal region. Hum Mol Genet. 1994 Apr;3(4):569–574. doi: 10.1093/hmg/3.4.569. [DOI] [PubMed] [Google Scholar]
  8. Chiti F., Webster P., Taddei N., Clark A., Stefani M., Ramponi G., Dobson C. M. Designing conditions for in vitro formation of amyloid protofilaments and fibrils. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3590–3594. doi: 10.1073/pnas.96.7.3590. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chou P. Y., Fasman G. D. Empirical predictions of protein conformation. Annu Rev Biochem. 1978;47:251–276. doi: 10.1146/annurev.bi.47.070178.001343. [DOI] [PubMed] [Google Scholar]
  10. Del Bo R., Comi G. P., Bresolin N., Castelli E., Conti E., Degiuli A., Ausenda C. D., Scarlato G. The apolipoprotein E epsilon4 allele causes a faster decline of cognitive performances in Down's syndrome subjects. J Neurol Sci. 1997 Jan;145(1):87–91. doi: 10.1016/s0022-510x(96)00249-3. [DOI] [PubMed] [Google Scholar]
  11. Diedrich J. F., Minnigan H., Carp R. I., Whitaker J. N., Race R., Frey W., 2nd, Haase A. T. Neuropathological changes in scrapie and Alzheimer's disease are associated with increased expression of apolipoprotein E and cathepsin D in astrocytes. J Virol. 1991 Sep;65(9):4759–4768. doi: 10.1128/jvi.65.9.4759-4768.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Exley C., Price N. C., Kelly S. M., Birchall J. D. An interaction of beta-amyloid with aluminium in vitro. FEBS Lett. 1993 Jun 21;324(3):293–295. doi: 10.1016/0014-5793(93)80137-j. [DOI] [PubMed] [Google Scholar]
  13. Garnier J., Osguthorpe D. J., Robson B. Analysis of the accuracy and implications of simple methods for predicting the secondary structure of globular proteins. J Mol Biol. 1978 Mar 25;120(1):97–120. doi: 10.1016/0022-2836(78)90297-8. [DOI] [PubMed] [Google Scholar]
  14. Gasset M., Baldwin M. A., Lloyd D. H., Gabriel J. M., Holtzman D. M., Cohen F., Fletterick R., Prusiner S. B. Predicted alpha-helical regions of the prion protein when synthesized as peptides form amyloid. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10940–10944. doi: 10.1073/pnas.89.22.10940. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Ghiso J., Wisniewski T., Frangione B. Unifying features of systemic and cerebral amyloidosis. Mol Neurobiol. 1994 Feb;8(1):49–64. doi: 10.1007/BF02778007. [DOI] [PubMed] [Google Scholar]
  16. Glenner G. G., Eanes E. D., Wiley C. A. Amyloid fibrils formed from a segment of the pancreatic islet amyloid protein. Biochem Biophys Res Commun. 1988 Sep 15;155(2):608–614. doi: 10.1016/s0006-291x(88)80538-2. [DOI] [PubMed] [Google Scholar]
  17. Glenner G. G., Wong C. W. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun. 1984 May 16;120(3):885–890. doi: 10.1016/s0006-291x(84)80190-4. [DOI] [PubMed] [Google Scholar]
  18. Goate A., Chartier-Harlin M. C., Mullan M., Brown J., Crawford F., Fidani L., Giuffra L., Haynes A., Irving N., James L. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature. 1991 Feb 21;349(6311):704–706. doi: 10.1038/349704a0. [DOI] [PubMed] [Google Scholar]
  19. Golabek A. A., Soto C., Vogel T., Wisniewski T. The interaction between apolipoprotein E and Alzheimer's amyloid beta-peptide is dependent on beta-peptide conformation. J Biol Chem. 1996 May 3;271(18):10602–10606. doi: 10.1074/jbc.271.18.10602. [DOI] [PubMed] [Google Scholar]
  20. Guijarro J. I., Sunde M., Jones J. A., Campbell I. D., Dobson C. M. Amyloid fibril formation by an SH3 domain. Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4224–4228. doi: 10.1073/pnas.95.8.4224. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Gustavsson A., Engström U., Westermark P. Normal transthyretin and synthetic transthyretin fragments form amyloid-like fibrils in vitro. Biochem Biophys Res Commun. 1991 Mar 29;175(3):1159–1164. doi: 10.1016/0006-291x(91)91687-8. [DOI] [PubMed] [Google Scholar]
  22. Hardy J. Amyloid, the presenilins and Alzheimer's disease. Trends Neurosci. 1997 Apr;20(4):154–159. doi: 10.1016/s0166-2236(96)01030-2. [DOI] [PubMed] [Google Scholar]
  23. Holtzman D. M., Bales K. R., Wu S., Bhat P., Parsadanian M., Fagan A. M., Chang L. K., Sun Y., Paul S. M. Expression of human apolipoprotein E reduces amyloid-beta deposition in a mouse model of Alzheimer's disease. J Clin Invest. 1999 Mar;103(6):R15–R21. doi: 10.1172/JCI6179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Horwich A. L., Weissman J. S. Deadly conformations--protein misfolding in prion disease. Cell. 1997 May 16;89(4):499–510. doi: 10.1016/s0092-8674(00)80232-9. [DOI] [PubMed] [Google Scholar]
  25. Hurle M. R., Helms L. R., Li L., Chan W., Wetzel R. A role for destabilizing amino acid replacements in light-chain amyloidosis. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5446–5450. doi: 10.1073/pnas.91.12.5446. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Hyman B. T., Terry R. D. Apolipoprotein E, A beta, and Alzheimer disease. J Neuropathol Exp Neurol. 1994 Sep;53(5):427–428. doi: 10.1097/00005072-199409000-00001. [DOI] [PubMed] [Google Scholar]
  27. Kelly J. W. Alternative conformations of amyloidogenic proteins govern their behavior. Curr Opin Struct Biol. 1996 Feb;6(1):11–17. doi: 10.1016/s0959-440x(96)80089-3. [DOI] [PubMed] [Google Scholar]
  28. Kindy M. S., Rader D. J. Reduction in amyloid A amyloid formation in apolipoprotein-E-deficient mice. Am J Pathol. 1998 May;152(5):1387–1395. [PMC free article] [PubMed] [Google Scholar]
  29. Kiuru S. Gelsolin-related familial amyloidosis, Finnish type (FAF), and its variants found worldwide. Amyloid. 1998 Mar;5(1):55–66. doi: 10.3109/13506129809007291. [DOI] [PubMed] [Google Scholar]
  30. Kurochkin I. V. Amyloidogenic determinant as a substrate recognition motif of insulin-degrading enzyme. FEBS Lett. 1998 May 8;427(2):153–156. doi: 10.1016/s0014-5793(98)00422-0. [DOI] [PubMed] [Google Scholar]
  31. Kwiatkowski D. J., Stossel T. P., Orkin S. H., Mole J. E., Colten H. R., Yin H. L. Plasma and cytoplasmic gelsolins are encoded by a single gene and contain a duplicated actin-binding domain. Nature. 1986 Oct 2;323(6087):455–458. doi: 10.1038/323455a0. [DOI] [PubMed] [Google Scholar]
  32. Levy-Lahad E., Bird T. D. Genetic factors in Alzheimer's disease: a review of recent advances. Ann Neurol. 1996 Dec;40(6):829–840. doi: 10.1002/ana.410400604. [DOI] [PubMed] [Google Scholar]
  33. Levy-Lahad E., Wasco W., Poorkaj P., Romano D. M., Oshima J., Pettingell W. H., Yu C. E., Jondro P. D., Schmidt S. D., Wang K. Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science. 1995 Aug 18;269(5226):973–977. doi: 10.1126/science.7638622. [DOI] [PubMed] [Google Scholar]
  34. Maury C. P., Nurmiaho-Lassila E. L., Rossi H. Amyloid fibril formation in gelsolin-derived amyloidosis. Definition of the amyloidogenic region and evidence of accelerated amyloid formation of mutant Asn-187 and Tyr-187 gelsolin peptides. Lab Invest. 1994 Apr;70(4):558–564. [PubMed] [Google Scholar]
  35. McLaughlin P. J., Gooch J. T., Mannherz H. G., Weeds A. G. Structure of gelsolin segment 1-actin complex and the mechanism of filament severing. Nature. 1993 Aug 19;364(6439):685–692. doi: 10.1038/364685a0. [DOI] [PubMed] [Google Scholar]
  36. Naiki H., Higuchi K., Nakakuki K., Takeda T. Kinetic analysis of amyloid fibril polymerization in vitro. Lab Invest. 1991 Jul;65(1):104–110. [PubMed] [Google Scholar]
  37. Namba Y., Tomonaga M., Kawasaki H., Otomo E., Ikeda K. Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer's disease and kuru plaque amyloid in Creutzfeldt-Jakob disease. Brain Res. 1991 Feb 8;541(1):163–166. doi: 10.1016/0006-8993(91)91092-f. [DOI] [PubMed] [Google Scholar]
  38. Pillot T., Goethals M., Najib J., Labeur C., Lins L., Chambaz J., Brasseur R., Vandekerckhove J., Rosseneu M. Beta-amyloid peptide interacts specifically with the carboxy-terminal domain of human apolipoprotein E: relevance to Alzheimer's disease. J Neurochem. 1999 Jan;72(1):230–237. doi: 10.1046/j.1471-4159.1999.0720230.x. [DOI] [PubMed] [Google Scholar]
  39. Prusiner S. B., McKinley M. P., Bowman K. A., Bolton D. C., Bendheim P. E., Groth D. F., Glenner G. G. Scrapie prions aggregate to form amyloid-like birefringent rods. Cell. 1983 Dec;35(2 Pt 1):349–358. doi: 10.1016/0092-8674(83)90168-x. [DOI] [PubMed] [Google Scholar]
  40. Ratnaswamy G., Koepf E., Bekele H., Yin H., Kelly J. W. The amyloidogenicity of gelsolin is controlled by proteolysis and pH. Chem Biol. 1999 May;6(5):293–304. doi: 10.1016/S1074-5521(99)80075-1. [DOI] [PubMed] [Google Scholar]
  41. Russo C., Angelini G., Dapino D., Piccini A., Piombo G., Schettini G., Chen S., Teller J. K., Zaccheo D., Gambetti P. Opposite roles of apolipoprotein E in normal brains and in Alzheimer's disease. Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15598–15602. doi: 10.1073/pnas.95.26.15598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Saunders A. M., Strittmatter W. J., Schmechel D., George-Hyslop P. H., Pericak-Vance M. A., Joo S. H., Rosi B. L., Gusella J. F., Crapper-MacLachlan D. R., Alberts M. J. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology. 1993 Aug;43(8):1467–1472. doi: 10.1212/wnl.43.8.1467. [DOI] [PubMed] [Google Scholar]
  43. Scherzinger E., Lurz R., Turmaine M., Mangiarini L., Hollenbach B., Hasenbank R., Bates G. P., Davies S. W., Lehrach H., Wanker E. E. Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo. Cell. 1997 Aug 8;90(3):549–558. doi: 10.1016/s0092-8674(00)80514-0. [DOI] [PubMed] [Google Scholar]
  44. Schupf N., Kapell D., Lee J. H., Zigman W., Canto B., Tycko B., Mayeux R. Onset of dementia is associated with apolipoprotein E epsilon4 in Down's syndrome. Ann Neurol. 1996 Nov;40(5):799–801. doi: 10.1002/ana.410400518. [DOI] [PubMed] [Google Scholar]
  45. Schägger H., von Jagow G. Tricine-sodium dodecyl sulfate-polyacrylamide gel electrophoresis for the separation of proteins in the range from 1 to 100 kDa. Anal Biochem. 1987 Nov 1;166(2):368–379. doi: 10.1016/0003-2697(87)90587-2. [DOI] [PubMed] [Google Scholar]
  46. Sherrington R., Rogaev E. I., Liang Y., Rogaeva E. A., Levesque G., Ikeda M., Chi H., Lin C., Li G., Holman K. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature. 1995 Jun 29;375(6534):754–760. doi: 10.1038/375754a0. [DOI] [PubMed] [Google Scholar]
  47. Soto C., Castaño E. M., Prelli F., Kumar R. A., Baumann M. Apolipoprotein E increases the fibrillogenic potential of synthetic peptides derived from Alzheimer's, gelsolin and AA amyloids. FEBS Lett. 1995 Sep 4;371(2):110–114. doi: 10.1016/0014-5793(95)00863-5. [DOI] [PubMed] [Google Scholar]
  48. Soto C., Golabek A., Wisniewski T., Castaño E. M. Alzheimer's beta-amyloid peptide is conformationally modified by apolipoprotein E in vitro. Neuroreport. 1996 Feb 29;7(3):721–725. doi: 10.1097/00001756-199602290-00010. [DOI] [PubMed] [Google Scholar]
  49. Strittmatter W. J., Saunders A. M., Schmechel D., Pericak-Vance M., Enghild J., Salvesen G. S., Roses A. D. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1977–1981. doi: 10.1073/pnas.90.5.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Strittmatter W. J., Weisgraber K. H., Huang D. Y., Dong L. M., Salvesen G. S., Pericak-Vance M., Schmechel D., Saunders A. M., Goldgaber D., Roses A. D. 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. 1993 Sep 1;90(17):8098–8102. doi: 10.1073/pnas.90.17.8098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Tagliavini F., Prelli F., Verga L., Giaccone G., Sarma R., Gorevic P., Ghetti B., Passerini F., Ghibaudi E., Forloni G. Synthetic peptides homologous to prion protein residues 106-147 form amyloid-like fibrils in vitro. Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9678–9682. doi: 10.1073/pnas.90.20.9678. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Taussig R., Gilman A. G. Mammalian membrane-bound adenylyl cyclases. J Biol Chem. 1995 Jan 6;270(1):1–4. doi: 10.1074/jbc.270.1.1. [DOI] [PubMed] [Google Scholar]
  53. Tjernberg L. O., Callaway D. J., Tjernberg A., Hahne S., Lilliehök C., Terenius L., Thyberg J., Nordstedt C. A molecular model of Alzheimer amyloid beta-peptide fibril formation. J Biol Chem. 1999 Apr 30;274(18):12619–12625. doi: 10.1074/jbc.274.18.12619. [DOI] [PubMed] [Google Scholar]
  54. Turnell W. G., Finch J. T. Binding of the dye congo red to the amyloid protein pig insulin reveals a novel homology amongst amyloid-forming peptide sequences. J Mol Biol. 1992 Oct 20;227(4):1205–1223. doi: 10.1016/0022-2836(92)90532-o. [DOI] [PubMed] [Google Scholar]
  55. Weeds A. G., Gooch J., McLaughlin P., Maury C. P. Variant plasma gelsolin responsible for familial amyloidosis (Finnish type) has defective actin severing activity. FEBS Lett. 1993 Nov 29;335(1):119–123. doi: 10.1016/0014-5793(93)80452-z. [DOI] [PubMed] [Google Scholar]
  56. Westermark P., Engström U., Johnson K. H., Westermark G. T., Betsholtz C. Islet amyloid polypeptide: pinpointing amino acid residues linked to amyloid fibril formation. Proc Natl Acad Sci U S A. 1990 Jul;87(13):5036–5040. doi: 10.1073/pnas.87.13.5036. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES