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. 1994 Nov;145(5):1030–1035.

Acceleration of Alzheimer's fibril formation by apolipoprotein E in vitro.

T Wisniewski 1, E M Castaño 1, A Golabek 1, T Vogel 1, B Frangione 1
PMCID: PMC1887417  PMID: 7977635

Abstract

Numerous studies have established a linkage between the apolipoprotein (apo) E4 allele and late-onset Alzheimer's disease. It remains unclear if apo E plays a direct role in the pathogenesis of Alzheimer's disease and what, if any, are its significant interactions with amyloid beta (A beta) and tau. Apo E has been found immunohistochemically in all types of amyloid deposits and apo E fragments have been isolated from amyloid. Furthermore, apo E has been shown to bind soluble A beta. It has been proposed that apo E acts to promote and/or modulate A beta fibril formation. It is well established that peptides homologous to A beta will form amyloid-like fibrils in solution. With the use of electron microscopy and a thioflavin T assay for fibril formation we found that apo E and apo E4 in particular enhance this spontaneous fibrillogenesis of A beta peptides under the in vitro conditions used. These in vitro data suggest that the apo E4 isoform is a risk factor for Alzheimer's disease that acts to accelerate a process that can occur in its absence.

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Selected References

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

  1. Arnett F. C. Histocompatibility typing in the rheumatic diseases. Diagnostic and prognostic implications. Rheum Dis Clin North Am. 1994 May;20(2):371–390. [PubMed] [Google Scholar]
  2. Barrow C. J., Yasuda A., Kenny P. T., Zagorski M. G. Solution conformations and aggregational properties of synthetic amyloid beta-peptides of Alzheimer's disease. Analysis of circular dichroism spectra. J Mol Biol. 1992 Jun 20;225(4):1075–1093. doi: 10.1016/0022-2836(92)90106-t. [DOI] [PubMed] [Google Scholar]
  3. Boyles J. K., Zoellner C. D., Anderson L. J., Kosik L. M., Pitas R. E., Weisgraber K. H., Hui D. Y., Mahley R. W., Gebicke-Haerter P. J., Ignatius M. J. A role for apolipoprotein E, apolipoprotein A-I, and low density lipoprotein receptors in cholesterol transport during regeneration and remyelination of the rat sciatic nerve. J Clin Invest. 1989 Mar;83(3):1015–1031. doi: 10.1172/JCI113943. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Burdick D., Soreghan B., Kwon M., Kosmoski J., Knauer M., Henschen A., Yates J., Cotman C., Glabe C. Assembly and aggregation properties of synthetic Alzheimer's A4/beta amyloid peptide analogs. J Biol Chem. 1992 Jan 5;267(1):546–554. [PubMed] [Google Scholar]
  5. Carlsson J., Armstrong V. W., Reiber H., Felgenhauer K., Seidel D. Clinical relevance of the quantification of apolipoprotein E in cerebrospinal fluid. Clin Chim Acta. 1991 Feb 15;196(2-3):167–176. doi: 10.1016/0009-8981(91)90070-s. [DOI] [PubMed] [Google Scholar]
  6. Castaño E. M., Ghiso J., Prelli F., Gorevic P. D., Migheli A., Frangione B. In vitro formation of amyloid fibrils from two synthetic peptides of different lengths homologous to Alzheimer's disease beta-protein. Biochem Biophys Res Commun. 1986 Dec 15;141(2):782–789. doi: 10.1016/s0006-291x(86)80241-8. [DOI] [PubMed] [Google Scholar]
  7. Clements A., Walsh D. M., Williams C. H., Allsop D. Effects of the mutations Glu22 to Gln and Ala21 to Gly on the aggregation of a synthetic fragment of the Alzheimer's amyloid beta/A4 peptide. Neurosci Lett. 1993 Oct 14;161(1):17–20. doi: 10.1016/0304-3940(93)90129-9. [DOI] [PubMed] [Google Scholar]
  8. Corder E. H., Saunders A. M., Strittmatter W. J., Schmechel D. E., Gaskell P. C., Small G. W., Roses A. D., Haines J. L., Pericak-Vance M. A. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993 Aug 13;261(5123):921–923. doi: 10.1126/science.8346443. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Haan J., Van Broeckhoven C., van Duijn C. M., Voorhoeve E., van Harskamp F., van Swieten J. C., Maat-Schieman M. L., Roos R. A., Bakker E. The apolipoprotein E epsilon 4 allele does not influence the clinical expression of the amyloid precursor protein gene codon 693 or 692 mutations. Ann Neurol. 1994 Sep;36(3):434–437. doi: 10.1002/ana.410360315. [DOI] [PubMed] [Google Scholar]
  11. Haass C., Schlossmacher M. G., Hung A. Y., Vigo-Pelfrey C., Mellon A., Ostaszewski B. L., Lieberburg I., Koo E. H., Schenk D., Teplow D. B. Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature. 1992 Sep 24;359(6393):322–325. doi: 10.1038/359322a0. [DOI] [PubMed] [Google Scholar]
  12. Handelmann G. E., Boyles J. K., Weisgraber K. H., Mahley R. W., Pitas R. E. Effects of apolipoprotein E, beta-very low density lipoproteins, and cholesterol on the extension of neurites by rabbit dorsal root ganglion neurons in vitro. J Lipid Res. 1992 Nov;33(11):1677–1688. [PubMed] [Google Scholar]
  13. Hilbich C., Kisters-Woike B., Reed J., Masters C. L., Beyreuther K. Substitutions of hydrophobic amino acids reduce the amyloidogenicity of Alzheimer's disease beta A4 peptides. J Mol Biol. 1992 Nov 20;228(2):460–473. doi: 10.1016/0022-2836(92)90835-8. [DOI] [PubMed] [Google Scholar]
  14. Kirschner D. A., Inouye H., Duffy L. K., Sinclair A., Lind M., Selkoe D. J. Synthetic peptide homologous to beta protein from Alzheimer disease forms amyloid-like fibrils in vitro. Proc Natl Acad Sci U S A. 1987 Oct;84(19):6953–6957. doi: 10.1073/pnas.84.19.6953. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. LeVine H., 3rd Thioflavine T interaction with synthetic Alzheimer's disease beta-amyloid peptides: detection of amyloid aggregation in solution. Protein Sci. 1993 Mar;2(3):404–410. doi: 10.1002/pro.5560020312. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Mahley R. W. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988 Apr 29;240(4852):622–630. doi: 10.1126/science.3283935. [DOI] [PubMed] [Google Scholar]
  17. Mahley R. W., Weisgraber K. H., Innerarity T. L. Interaction of plasma lipoproteins containing apolipoproteins B and E with heparin and cell surface receptors. Biochim Biophys Acta. 1979 Oct 26;575(1):81–91. doi: 10.1016/0005-2760(79)90133-4. [DOI] [PubMed] [Google Scholar]
  18. Naiki H., Higuchi K., Hosokawa M., Takeda T. Fluorometric determination of amyloid fibrils in vitro using the fluorescent dye, thioflavin T1. Anal Biochem. 1989 Mar;177(2):244–249. doi: 10.1016/0003-2697(89)90046-8. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. Nathan B. P., Bellosta S., Sanan D. A., Weisgraber K. H., Mahley R. W., Pitas R. E. Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro. Science. 1994 May 6;264(5160):850–852. doi: 10.1126/science.8171342. [DOI] [PubMed] [Google Scholar]
  21. Poduri A., Gearing M., Rebeck G. W., Mirra S. S., Tigges J., Hyman B. T. Apolipoprotein E4 and beta amyloid in senile plaques and cerebral blood vessels of aged rhesus monkeys. Am J Pathol. 1994 Jun;144(6):1183–1187. [PMC free article] [PubMed] [Google Scholar]
  22. Poirier J., Baccichet A., Dea D., Gauthier S. Cholesterol synthesis and lipoprotein reuptake during synaptic remodelling in hippocampus in adult rats. Neuroscience. 1993 Jul;55(1):81–90. doi: 10.1016/0306-4522(93)90456-p. [DOI] [PubMed] [Google Scholar]
  23. Prelli F., Pras M., Shtrasburg S., Frangione B. Characterization of high molecular weight amyloid A proteins. Scand J Immunol. 1991 Jun;33(6):783–786. doi: 10.1111/j.1365-3083.1991.tb02553.x. [DOI] [PubMed] [Google Scholar]
  24. Rebeck G. W., Reiter J. S., Strickland D. K., Hyman B. T. Apolipoprotein E in sporadic Alzheimer's disease: allelic variation and receptor interactions. Neuron. 1993 Oct;11(4):575–580. doi: 10.1016/0896-6273(93)90070-8. [DOI] [PubMed] [Google Scholar]
  25. Schmechel D. E., Saunders A. M., Strittmatter W. J., Crain B. J., Hulette C. M., Joo S. H., Pericak-Vance M. A., Goldgaber D., Roses A. D. Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9649–9653. doi: 10.1073/pnas.90.20.9649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Schächter F., Faure-Delanef L., Guénot F., Rouger H., Froguel P., Lesueur-Ginot L., Cohen D. Genetic associations with human longevity at the APOE and ACE loci. Nat Genet. 1994 Jan;6(1):29–32. doi: 10.1038/ng0194-29. [DOI] [PubMed] [Google Scholar]
  27. Seubert P., Vigo-Pelfrey C., Esch F., Lee M., Dovey H., Davis D., Sinha S., Schlossmacher M., Whaley J., Swindlehurst C. Isolation and quantification of soluble Alzheimer's beta-peptide from biological fluids. Nature. 1992 Sep 24;359(6393):325–327. doi: 10.1038/359325a0. [DOI] [PubMed] [Google Scholar]
  28. Shoji M., Golde T. E., Ghiso J., Cheung T. T., Estus S., Shaffer L. M., Cai X. D., McKay D. M., Tintner R., Frangione B. Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science. 1992 Oct 2;258(5079):126–129. doi: 10.1126/science.1439760. [DOI] [PubMed] [Google Scholar]
  29. Snow A. D., Willmer J., Kisilevsky R. Sulfated glycosaminoglycans: a common constituent of all amyloids? Lab Invest. 1987 Jan;56(1):120–123. [PubMed] [Google Scholar]
  30. Strittmatter W. J., Weisgraber K. H., Goedert M., Saunders A. M., Huang D., Corder E. H., Dong L. M., Jakes R., Alberts M. J., Gilbert J. R. Hypothesis: microtubule instability and paired helical filament formation in the Alzheimer disease brain are related to apolipoprotein E genotype. Exp Neurol. 1994 Feb;125(2):163–174. doi: 10.1006/exnr.1994.1019. [DOI] [PubMed] [Google Scholar]
  31. Vogel T., Weisgraber K. H., Zeevi M. I., Ben-Artzi H., Levanon A. Z., Rall S. C., Jr, Innerarity T. L., Hui D. Y., Taylor J. M., Kanner D. Human apolipoprotein E expression in Escherichia coli: structural and functional identity of the bacterially produced protein with plasma apolipoprotein E. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8696–8700. doi: 10.1073/pnas.82.24.8696. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Waring S. C., O'Brien P. C., Kurland L. T., Thibodeau S. N., Tsai M. S., Petersen R. C., Esteban-Santillan C. E. Apolipoprotein E allele in Chamorros with amyotrophic lateral sclerosis/parkinsonism-dementia complex. Lancet. 1994 Mar 5;343(8897):611–611. doi: 10.1016/s0140-6736(94)91568-7. [DOI] [PubMed] [Google Scholar]
  33. Weisgraber K. H. Apolipoprotein E: structure-function relationships. Adv Protein Chem. 1994;45:249–302. doi: 10.1016/s0065-3233(08)60642-7. [DOI] [PubMed] [Google Scholar]
  34. Wisniewski T., Castano E., Ghiso J., Frangione B. Cerebrospinal fluid inhibits Alzheimer beta-amyloid fibril formation in vitro. Ann Neurol. 1993 Oct;34(4):631–633. doi: 10.1002/ana.410340422. [DOI] [PubMed] [Google Scholar]
  35. Wisniewski T., Frangione B. Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid. Neurosci Lett. 1992 Feb 3;135(2):235–238. doi: 10.1016/0304-3940(92)90444-c. [DOI] [PubMed] [Google Scholar]
  36. Wisniewski T., Frangione B. Molecular biology of Alzheimer's amyloid--Dutch variant. Mol Neurobiol. 1992 Spring;6(1):75–86. doi: 10.1007/BF02935567. [DOI] [PubMed] [Google Scholar]
  37. Wisniewski T., Ghiso J., Frangione B. Alzheimer's disease and soluble A beta. Neurobiol Aging. 1994 Mar-Apr;15(2):143–152. doi: 10.1016/0197-4580(94)90105-8. [DOI] [PubMed] [Google Scholar]
  38. Wisniewski T., Ghiso J., Frangione B. Peptides homologous to the amyloid protein of Alzheimer's disease containing a glutamine for glutamic acid substitution have accelerated amyloid fibril formation. Biochem Biophys Res Commun. 1991 Sep 30;179(3):1247–1254. doi: 10.1016/0006-291x(91)91706-i. [DOI] [PubMed] [Google Scholar]
  39. Yu C. E., Payami H., Olson J. M., Boehnke M., Wijsman E. M., Orr H. T., Kukull W. A., Goddard K. A., Nemens E., White J. A. The apolipoprotein E/CI/CII gene cluster and late-onset Alzheimer disease. Am J Hum Genet. 1994 Apr;54(4):631–642. [PMC free article] [PubMed] [Google Scholar]

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