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Cited by 28Alzheimer's disease research and treatmentsCholesterol and Lipid MetabolismLipoproteins and Cardiovascular Health

Apolipoprotein E secreted by astrocytes forms antiparallel dimers in discoidal lipoproteins

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Strickland, Michael R., Rau, Michael J., Summers, Brock, Basore, Katherine, Wulf, John, Jiang, Hong, Chen, Yun, Ulrich, Jason D. +5 more·2024·Neuron
DOI 10.1016/j.neuron.2023.12.018PMC PMC10994765
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Abstract

The Apolipoprotein E gene (APOE) is of great interest due to its role as a risk factor for late-onset Alzheimer's disease. ApoE is secreted by astrocytes in the central nervous system in high-density lipoprotein (HDL)-like lipoproteins. Structural models of lipidated ApoE of high resolution could aid in a mechanistic understanding of how ApoE functions in health and disease. Using monoclonal Fab and F(ab')2 fragments, we characterize the structure of lipidated ApoE on astrocyte-secreted lipoproteins. Our results provide support for the "double-belt" model of ApoE in nascent discoidal HDL-like lipoproteins, where two ApoE proteins wrap around the nanodisc in an antiparallel conformation. We further show that lipidated, recombinant ApoE accurately models astrocyte-secreted ApoE lipoproteins. Cryogenic electron microscopy of recombinant lipidated ApoE further supports ApoE adopting antiparallel dimers in nascent discoidal lipoproteins.

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Crossref · 10.1016/j.neuron.2023.12.018

Cites

16 of 16 references verified0 citation errors · 0 not checkable

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Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In the cerebrospinal fluid (CSF), HDL-like LNPs predominate, although their major protein constituent is ApoE, not ApoA-I.

    “In the cerebrospinal fluid (CSF), HDL-like LNPs predominate, although their major protein constituent is ApoE, not ApoA-I.11, 12”

    From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [12]

    The Introduction (page unavailable) says ApoE is present in HDL-like lipoproteins in the CNS and describes astrocyte-secreted ApoE particles as HDL-like. It does not establish that HDL-like particles predominate specifically in CSF or that ApoE, rather than ApoA-I, is their major protein constituent. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • The resulting nanoparticles typically lack the characteristic lipid complexity of their plasma- or CSF-derived counterparts.

    “the resulting nanoparticles typically lack the characteristic lipid complexity of their plasma- or CSF-derived counterparts.12, 26”

    From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [12]

    In “Lipidated, recombinant ApoE lipoproteins resemble astrocyte-secreted ApoE lipoproteins” (page not available), the paper describes nanoparticles assembled from recombinant ApoE and a selected artificial lipid, supporting the claim that these particles have a limited lipid composition. It does not compare their lipid complexity with plasma- or CSF-derived particles or establish that this is typical of resulting nanoparticles generally. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Cryo-electron microscopy of APOE lipoprotein particles secreted from astrocytes in culture has revealed that APOE forms an anti-parallel dimer that wraps a discoidal lipoparticle in a 'double-belt' configuration.

    “Cryo-electron microscopy of APOE lipoprotein particles secreted from astrocytes in culture has revealed that APOE forms an anti-parallel dimer that wraps a discoidal lipoparticle in a ‘double-belt’ configuration101.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [101]

    The Results (Figure 1B; page not given) report that astrocyte-secreted ApoE forms antiparallel dimers on discoidal particles, supporting the double-belt description. But those particles were examined by negative-stain TEM; the cryo-EM analysis in the section “Cryo-EM of recombinant ApoE lipoproteins” used recombinant particles, not particles secreted by cultured astrocytes. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Protocols have been developed to formulate apoprotein sources into LNPs.

    “While protocols have been developed to formulate these apoprotein sources into LNPs (a process that is often referred to as “lipidation”), the resulting nanoparticles typically lack the characteristic lipid complexity of their plasma- or CSF-derived counterparts.12, 26”

    From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [12]

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Cites

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Research works printed but not linked: 7

  1. Coon, K.D., Myers, A.J., Craig, D.W., Webster, J.A., Pearson, J.V., Lince, D.H., Zismann, V.L., Beach, T.G., Leung, D., Bryden, L., et al. (2007). A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer's disease. J. Clin. Psychiatry 68, 613-618.
  2. Corder, E.H., Saunders, A.M., Strittmatter, W.J., Schmechel, D.E., Gaskell, P.C., Small, G.W., Roses, A.D., Haines, J.L., and Pericak- Vance, M.A. (1993). Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921-923.
  3. Bales, K.R., Verina, T., Cummins, D.J., Du, Y., Dodel, R.C., Saura, J., Fishman, C.E., DeLong, C.A., Piccardo, P., Petegnief, V., et al. (1999). Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. USA 96, 15233-15238.
  4. Brussel, V.U., Efremov, R.G., Gatsogiannis, C., and Raunser, S. (2017). Lipid Nanodiscs as a Tool for High-Resolution Structure Determination of Membrane Proteins by Single-Particle Cryo-EM, First Edition (Elsevier Inc.).
  5. Verghese, P.B., Castellano, J.M., Garai, K., Wang, Y., Jiang, H., Shah, A., Bu, G., Frieden, C., and Holtzman, D.M. (2013). ApoE influences amyloid- $b$ (A$b$) clearance despite minimal apoE/A$b$ association in physio- logical conditions. Proc. Natl. Acad. Sci. USA 110, E1807-E1816.
  6. Stark, H. (2010). GraFix: Stabilization of Fragile Macromolecular Complexes for Single Particle Cryo-EM (Elsevier Masson SAS).
  7. Borhani, D.W., Rogers, D.P., Engler, J.A., and Brouillette, C.G. (1997). Crystal structure of truncated human apolipoprotein A-I suggests a lipid- bound conformation. Proc. Natl. Acad. Sci. USA 94, 12291-12296.

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Authors
Strickland, M. R., Rau, M. J., Summers, B., Basore, K., Wulf, J., Jiang, H., Chen, Y., Ulrich, J. D., Randolph, G. J., Zhang, R., Fitzpatrick, J. A. J., Cashikar, A. G., & Holtzman, D. M.
Affiliations
  • Washington University in St. Louis (US)
  • Hope Center for Neurological Disorders (US)
Corresponding author
Holtzman, David M.
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2024-04
Volume
112
Issue
7
Pages
1100-1109.e5
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2023.12.018
PMC
PMC10994765
OpenAlex
W4391135250
Cited by
28
References
16
Citations by year
2026: 13 · 2025: 10 · 2024: 5
FWCI
7.24
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
Funders
  • NIH (1U19AG069701, RF1NS090934, T32AG058518)
  • Washington University in St. Louis
  • JPB Foundation
  • University of Washington
  • National Science Foundation (1U19AG069701, RF1NS090934, DGE-1745038)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Keywords
apolipoprotein E, astrocytes, high-density lipoprotein, antiparallel dimer, lipoprotein structure, Alzheimer's disease risk, monoclonal antibody fragments, cryo-electron microscopy
MeSH terms
Apolipoproteins E, Astrocytes, Central Nervous System, Lipoproteins, Lipoproteins, HDL, Apolipoprotein E3, Apolipoprotein E4

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