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Cited by 298Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Apolipoprotein E: Structural Insights and Links to Alzheimer Disease Pathogenesis

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Chen, Yun, Strickland, Michael R., Soranno, Andrea, Holtzman, David M.·2021·Neuron
DOI 10.1016/j.neuron.2020.10.008PMC PMC7931158
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Abstract

Apolipoprotein E (ApoE) is of great interest due to its role as a cholesterol/lipid transporter in the central nervous system (CNS) and as the most influential genetic risk factor for Alzheimer disease (AD). Work over the last four decades has given us important insights into the structure of ApoE and how this might impact the neuropathology and pathogenesis of AD. In this review, we highlight the history and progress in the structural and molecular understanding of ApoE and discuss how these studies on ApoE have illuminated the physiology of ApoE, receptor binding, and interaction with amyloid-β (Aβ). We also identify future areas of study needed to advance our understanding of how ApoE influences neurodegeneration.

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  • The single amino acid changes in the different APOE isoforms result in slightly different structures, which have a strikingly large effect on the binding affinities of APOE to lipids, Aβ and receptors.

    “The single amino acid changes in the different APOE isoforms result in slightly different structures, which have a strikingly large effect on the binding affinities of APOE to lipids, Aβ and receptors99,111,116,140.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [99]

    The Historical Progress section says single amino acid substitutions can dramatically change ApoE lipoprotein characteristics and binding properties, and the ApoE Receptors section reports dramatically reduced LDLR binding by ApoE2 (page numbers unavailable). However, the Conclusion says structural interactions *may* drive isoform-specific binding to receptors, lipids and Aβ. The ApoE–Aβ section describes findings that vary with lipidation state, so the claim overstates a uniformly large, established effect on all three binding affinities. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The N-terminal domain of APOE consists of four amphipathic alpha helices that form a bundle in solution.

    “The N-terminal domain consists of four amphipathic alpha helices that form a bundle in solution (Chen et al., 2021).”

    From APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size (2024) · cites this paper as Chen et al., 2021

    The Historical Progress in Understanding ApoE Structure section (page unavailable) describes the N-terminal domain as a four-helix bundle and discusses its structure before lipid association. Our copy does not establish that all four N-terminal helices are amphipathic or explicitly say that the bundle forms in solution; its explicit discussion of amphipathic helices concerns the C-terminal domain. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • The arginine at position 112 in ApoE4 is predicted to promote an interaction between the N- and C-terminal domains (domain interaction) that is absent in ApoE3 and ApoE2.

    “The arginine at position 112 in ApoE4 is predicted to promote an interaction between the N-and C-terminal domains (domain interaction) that is absent in ApoE3 and ApoE2 23,26,27 .”

    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 [23]

  • APOE itself has been shown to form aggregates, particularly in its non-lipidated state.

    “however, APOE itself has also been shown to form aggregates, particularly in its non-lipidated state99,134,135 (Fig. 2).”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [99]

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Cited by

Sorted by citations

Authors
Chen, Y., Strickland, M. R., Soranno, A., & Holtzman, D. M.
Affiliations
Washington University in St. Louis (US)
Corresponding author
Holtzman, David M.
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2021-01
Volume
109
Issue
2
Pages
205-221
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2020.10.008
PMC
PMC7931158
OpenAlex
W3104621343
Cited by
298
References
44
Citations by year
2026: 39 · 2025: 70 · 2024: 59 · 2023: 64 · 2022: 41 · 2021: 24
FWCI
4.11
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • JPB Foundation
  • National Science Foundation
  • Ruth K. Broad Biomedical Research Foundation
  • National Institutes of Health
  • Alzheimer's Association
  • Cure Alzheimer's Fund
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
apolipoprotein E, Alzheimer's disease, cholesterol transport, lipid transport, genetic risk factors, amyloid-beta, neurodegeneration, Alzheimer disease pathogenesis
MeSH terms
Alzheimer Disease, Animals, Apolipoproteins E, Brain, Humans, Receptors, LDL, Protein Structure, Secondary, Protein Transport, Protein Multimerization

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