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Cited by 73Alzheimer's disease research and treatmentsLipid Membrane Structure and BehaviorLipoproteins and Cardiovascular Health

Apolipoprotein E associated with reconstituted high‐density lipoprotein‐like particles is protected from aggregation

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Hubin, Ellen, Verghese, Philip B., van Nuland, Nico, Broersen, Kerensa·2019·FEBS Letters
DOI 10.1002/1873-3468.13428PMC PMC6617784
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Abstract

Apolipoprotein E (APOE) genotype determines Alzheimer's disease (AD) susceptibility, with the APOE ε4 allele being an established risk factor for late‐onset AD. The ApoE lipidation status has been reported to impact amyloid‐beta (Aβ) peptide metabolism. The details of how lipidation affects ApoE behavior remain to be elucidated. In this study, we prepared lipid‐free and lipid‐bound ApoE particles, mimicking the high‐density lipoprotein particles found in vivo, for all three isoforms (ApoE2, ApoE3, and ApoE4) and biophysically characterized them. We find that lipid‐free ApoE in solution has the tendency to aggregate in vitro in an isoform‐dependent manner under near‐physiological conditions and that aggregation is impeded by lipidation of ApoE.

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  1. [1]Dieckmann M, Dietrich MF and Herz J (2010) Lipoprotein receptors‐an evolutionarily ancient multifunctional receptor family. Biol Chem 391, 1341– 1363. 20868222 PMC3529395
  2. [4]Mahley RW (1988) Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 240, 622– 630. 3283935
  3. [6]Strittmatter WJ, Saunders AM, Schmechel D, Pericak‐Vance M, Enghild G, Salvesen S and Roses AD (1993) 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 USA 90, 1977– 1981. 8446617 PMC46003
  4. [8]Namba Y, Tomonaga M, Kawasaki H, Otomo E and Ikeda K (1991) Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer's disease and kuru plaque amyloid in Creutzfeldt‐Jakob disease. Brain Res 54, 163– 166. 2029618
  5. [9]Mahley RW, Weisgraber KH and Huang Y (2006) Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease. Proc Natl Acad Sci USA 103, 5644– 5651. 16567625 PMC1414631
  6. [10]Bu G (2009) Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy. Nat Rev Neurosci 10, 333– 344. 19339974 PMC2908393
  7. [11]Iurescia S, Fioretti D, Mangialasche F and Rinaldi M (2010) The pathological cross talk between apolipoprotein E and amyloid‐beta peptide in Alzheimer's disease: emerging gene‐based therapeutic approaches. J Alzheimers Dis 21, 35– 48. 20182014
  8. [12]Liu CC, Kanekiyo T, Xu H and Bu G (2013) Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9, 106– 118. 23296339 PMC3726719
  9. [13]Huang Y (2010) Abeta‐independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer's disease. Trends Mol Med 16, 287– 294. 20537952
  10. [14]Weisgraber KH, Rall SC and Mahley RW (1981) Human E apoprotein heterogeneity. Cysteine‐arginine interchanges in the amino acid sequence of the apo‐E isoforms. J Biol Chem 256, 9077– 9083. 7263700
  11. [16]Hauser PS, Narayanaswami V and Ryan RO (2011) Apolipoprotein E: from lipid transport to neurobiology. Prog Lipid Res 50, 62– 74. 20854843 PMC3022415
  12. [18]Innerarity TL, Pitas RE and Mahley RW (1979) Binding of arginine‐rich (E) apoprotein after recombination with phospholipid vesicles to the low density lipoprotein receptors of fibroblasts. J Biol Chem 254, 4186– 4190. 220235
  13. [19]Carter DB (2005) The interaction of amyloid‐beta with ApoE. Subcell Biochem 38, 255– 272. 15709483
  14. [21]Stratman NC, Castle CK, Taylor BM, Epps DE, Melchior GW and Carter DB (2005) Isoform‐specific interactions of human apolipoprotein E to an intermediate conformation of human Alzheimer amyloid‐beta peptide. Chem Phys Lipids 137, 52– 61. 16140289
  15. [25]Wildsmith KR, Holley M, Savage JC, Skerrett R and Landreth GE (2013) Evidence for impaired amyloid β clearance in Alzheimer's disease. Alzheimers Res Ther 5, 33. 23849219 PMC3978761
  16. [32]Verghese PB, Castellano JM, Garai K, Wang Y, Jiang H, Shah A, Bu G, Frieden C and Holtzman DM (2013) ApoE influences amyloid‐β (Aβ) clearance despite minimal apoE/Aβ association in physiological conditions. Proc Natl Acad Sci USA 110, E1807– E1816. 23620513 PMC3651443
  17. [33]Perugini MA, Schuck P and Howlett GJ (2000) Self‐association of human apolipoprotein E3 and E4 in the presence and absence of phospholipid. J Biol Chem 275, 36758– 36765. 10970893
  18. [34]Garai K and Frieden C (2010) The association−dissociation behavior of the ApoE proteins: kinetic and equilibrium studies. Biochemistry 49, 9533– 9541. 20923231 PMC3038193
  19. [35]Chou CY, Lin YL, Huang YC, Sheu SY, Lin TH, Tsay HJ, Chang GG and Shiao MS (2005) Structural variation in human apolipoprotein E3 and E4: secondary structure, tertiary structure, and size distribution. Biophys J 88, 455– 466. 15475580 PMC1305022
  20. [37]Matz CE and Jonas A (1982) Micellar complexes of human apolipoprotein A‐I with phosphatidylcholines and cholesterol prepared from cholate‐lipid dispersions. J Biol Chem 257, 4535– 4540. 6802835
  21. [38]Jonas A, Sweeney SA and Herbert PN (1984) Discoidal complexes of A and C apolipoprotein with lipids and their reactions with lecithin: cholesterol acyltransferase. J Biol Chem 259, 6369– 6375. 6427214
  22. [39]Wilkins MR, Gasteiger E, Bairoch A, Sanchez JC, Williams KL, Appel RD and Hochstrasser DF (1999) Protein identification and analysis tools in the ExPASy server. Methods Mol Biol 112, 531– 552. 10027275
  23. [40]Zhang L, Song J, Newhouse Y, Zhang S, Weisgraber KH and Ren G (2010) An optimized negative‐staining protocol of electron microscopy for apoE4 POPC lipoprotein. J Lipid Res 51, 1228– 1236. 19965615 PMC2853450
  24. [41]Sreerama N and Woody RW (2000) Estimation of protein secondary structure from circular dichroism spectra: comparison of CONTIN, SELCON, and CDSSTR methods with an expanded reference set. Anal Biochem 287, 252– 260. 11112271
  25. [42]Whitmore L and Wallace BA (2008) Protein secondary structure analyses from circular dichroism spectroscopy: methods and reference databases. Biopolymers 89, 392– 400. 17896349
  26. [44]Yamauchi K, Tozuka M, Nakabayashi T, Sugano M, Hidaka H, Kondo Y and Katsuyama T (1999) Apolipoprotein E in cerebrospinal fluid: relation to phenotype and plasma apolipoprotein E concentrations. Clin Chem 45, 497– 504. 10102909
  27. [45]Morrow JA, Segall ML, Lund‐Katz S, Phillips MC, Knapp M, Rupp B and Weisgraber KH (2000) Differences in stability among the human apolipoprotein E isoforms determined by the amino‐terminal domain. Biochemistry 39, 11657– 11666. 10995233
  28. [46]Hatters DM and Howlett GJ (2002) The structural basis for amyloid formation by plasma apolipoproteins: a review. Eur Biophys J 31, 2– 8. 12046894
  29. [49]Fan D, Li Q, Korando L, Jerome WG and Wang J (2004) A monomeric human apolipoprotein E carboxyl‐terminal domain. Biochemistry 43, 5055– 5064. 15109264
  30. [52]Garai K, Baban B and Frieden C (2011) Dissociation of apolipoprotein E oligomers to monomer is required for high‐affinity binding to phospholipid vesicles. Biochemistry 50, 2550– 2558. 21322570 PMC3088999
  31. [53]Gong EL, Nichols AV, Weisgraber KH, Forte TM, Shore VG and Blanche PJ (1989) Discoidal complexes containing apolipoprotein E and their transformation by lecithin‐cholesterol acyltransferase. Biochim Biophys Acta 1006, 317– 328. 2597674

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Authors
Hubin, E., Verghese, P. B., van Nuland, N., & Broersen, K.
Affiliations
  • Vrije Universiteit Brussel (BE)
  • Washington University in St. Louis (US)
  • Structural Biology Brussels Department of Biotechnology (DBIT) Vrije Universiteit Brussel (VUB) Belgium
  • University of Twente (NL)
Corresponding author
Broersen, Kerensa
ORCID
Venue
FEBS Letters
Publisher
Wiley
Published
2019-05-27
Volume
593
Issue
11
Pages
1144-1153
ISSN
  • 0014-5793 (ISSN-L)
  • 1873-3468
DOI
10.1002/1873-3468.13428
PMC
PMC6617784
OpenAlex
W2944501913
Cited by
73
References
22
Citations by year
2026: 8 · 2025: 9 · 2024: 4 · 2023: 13 · 2022: 25 · 2021: 8 · 2020: 4 · 2019: 2
FWCI
6.66
Type
journal article
Language
en
Open access
Licence
Locations
  • FEBS Letters (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • University of Twente Research Information (acceptedVersion, cc-by)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
  • University of Twente Research Information (submittedVersion, cc-by)
Funders
Internationale Stichting Alzheimer Onderzoek
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Keywords
apolipoprotein E, lipid modification, protein aggregation, APOE isoforms, APOE ε4, Alzheimer's disease, amyloid-beta metabolism
MeSH terms
Apolipoproteins E, Humans, Lipoproteins, HDL, Liposomes, Protein Multimerization

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