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Cited by 47Alzheimer's disease research and treatmentsProtein Structure and DynamicsDementia and Cognitive Impairment Research

The Molecular Basis for Apolipoprotein E4 as the Major Risk Factor for Late-Onset Alzheimer's Disease

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Raulin, Ana-Caroline, Kraft, Lucas, Al-Hilaly, Youssra K., Xue, Wei-Feng, McGeehan, John E., Atack, John R., Serpell, Louise·2019·Journal of Molecular Biology
DOI 10.1016/j.jmb.2019.04.019PMC PMC6556554
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Abstract

Apolipoprotein E4 (ApoE4) is one of three (E2, E3 and E4) human isoforms of an α-helical, 299-amino-acid protein. Homozygosity for the ε4 allele is the major genetic risk factor for developing late-onset Alzheimer's disease (AD). ApoE2, ApoE3 and ApoE4 differ at amino acid positions 112 and 158, and these sequence variations may confer conformational differences that underlie their participation in the risk of developing AD. Here, we compared the shape, oligomerization state, conformation and stability of ApoE isoforms using a range of complementary biophysical methods including small-angle x-ray scattering, analytical ultracentrifugation, circular dichroism, x-ray fiber diffraction and transmission electron microscopy We provide an in-depth and definitive study demonstrating that all three proteins are similar in stability and conformation. However, we show that ApoE4 has a propensity to polymerize to form wavy filaments, which do not share the characteristics of cross-β amyloid fibrils. Moreover, we provide evidence for the inhibition of ApoE4 fibril formation by ApoE3. This study shows that recombinant ApoE isoforms show no significant differences at the structural or conformational level. However, self-assembly of the ApoE4 isoform may play a role in pathogenesis, and these results open opportunities for uncovering new triggers for AD onset.

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  • The aggregation-prone behavior of ApoE can complicate the interpretation of thermal stability data.

    “Lipid-free ApoE readily self-associates through hydrophobic interactions, and this aggregation-prone behavior can complicate the interpretation of thermal stability data 41,63 .”

    From Utilizing a cell culture based novel cellular thermal shift assay to understand the isoform-dependent thermal stability of ApoE variants (2026) · cites this paper as [63]

    The Discussion (page unavailable) links ApoE4’s measured loss of stability under high-temperature conditions to its propensity to polymerize, and the Thermal denaturation methods report irreversible unfolding. These passages support a connection between aggregation and thermal-stability measurements, but do not explicitly say that aggregation complicates interpretation of the data. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • Lipid-free ApoE readily self-associates through hydrophobic interactions.

    “Lipid-free ApoE readily self-associates through hydrophobic interactions, and this aggregation-prone behavior can complicate the interpretation of thermal stability data 41,63 .”

    From Utilizing a cell culture based novel cellular thermal shift assay to understand the isoform-dependent thermal stability of ApoE variants (2026) · cites this paper as [63]

    The Results section (‘All three ApoE isoforms show similar size and shape’; page unavailable) reports that recombinant ApoE2, E3 and E4 form tetramers in solution. The Results section on ApoE4 assembly reports rapid further self-assembly for ApoE4, but much less for ApoE2 and ApoE3. The copy does not establish that hydrophobic interactions drive this association, so it supports the self-association point but not the stated mechanism. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Authors
Raulin, A.-C., Kraft, L., Al-Hilaly, Y. K., Xue, W.-F., McGeehan, J. E., Atack, J. R., & Serpell, L.
Affiliations
  • University of Sussex (GB)
  • University of Kent (GB)
  • University of Portsmouth (GB)
Corresponding author
Serpell, Louise
ORCID
Venue
Journal of Molecular Biology
Publisher
Elsevier BV
Published
2019-05
Volume
431
Issue
12
Pages
2248-2265
ISSN
0022-2836 (ISSN-L)
DOI
10.1016/j.jmb.2019.04.019
PMC
PMC6556554
OpenAlex
W2943773301
Cited by
47
References
14
Citations by year
2026: 4 · 2025: 4 · 2024: 4 · 2023: 13 · 2022: 8 · 2021: 2 · 2020: 11 · 2019: 1
FWCI
3.77
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Molecular Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • Kent Academic Repository (University of Kent) (acceptedVersion)
  • Sussex Research Online (University of Sussex) (submittedVersion, cc-by)
  • Figshare (submittedVersion, cc-by)
Funders
  • Biotechnology and Biological Sciences Research Council (3657/1)
  • Alzheimer’s Research UK
  • University of Sussex
  • Medical Research Council (MR/S026495/1)
  • Alzheimer's Society
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
APOE ε4, apolipoprotein E isoforms, late-onset Alzheimer's disease, genetic risk factors, protein conformation, protein stability, oligomerization, fibril formation inhibition, APOE3, self-assembly, amyloid fibrils
MeSH terms
Alzheimer Disease, Amyloid, Humans, Protein Conformation, Risk Factors, Protein Isoforms, Apolipoprotein E4, Protein Multimerization, Protein Stability

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