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Cited by 84Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Apolipoprotein E: isoform specific differences in tertiary structure and interaction with amyloid-β in human Alzheimer brain

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Jones, Phillip B., Adams, Kenneth W., Rozkalne, Anete, Spires-Jones, Tara L., Hshieh, Tammy T., Hashimoto, Tadafumi, von Armin, Christine A. F., Mielke, Mathew +2 more·2011·PLoS ONE
DOI 10.1371/journal.pone.0014586PMC PMC3031506
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Abstract

We applied a novel application of FLIM-FRET to in situ measurement and quantification of protein interactions to explore isoform specific differences in Aβ-ApoE interaction and ApoE tertiary conformation in senile plaques in human Alzheimer brain. ApoE3 interacts more closely with Aβ than ApoE4, but a greater proportion of Aβ molecules within plaques are decorated with ApoE4 than ApoE3, lending strong support to the hypothesis that isoform specific differences in ApoE are linked with Aβ deposition. We found an increased number of ApoE N-terminal fragments in ApoE4 plaques, consistent with the observation that ApoE4 is more easily cleaved than ApoE3. In addition, we measured a small but significant isoform specific difference in ApoE domain interaction. Based on our in situ data, supported by traditional biochemical data, we propose a pathway by which isoform specific conformational differences increase the level of cleavage at the hinge region of ApoE4, leading to a loss of ApoE function to mediate clearance of Aβ and thereby increase the risk of AD for carriers of the APOEε4 allele.

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  • The truncated apoE4 variant apoE4[Δ(166-299)] has a similar molecular weight to carboxyl-terminal truncated apoE4 fragments found in the brain of Alzheimer disease patients.

    “which has a similar molecular weight as carboxyl-terminal truncated apoE4 fragments found in the brain of AD patients (54,55)”

    From Molecular Basis for Increased Risk for Late-onset Alzheimer Disease Due to the Naturally Occurring L28P Mutation in Apolipoprotein E4 (2014) · cites this paper as [55]

    The Results (page unavailable) report 17–34 kDa apoE fragments in Alzheimer brain and identify that band as a mixture containing N-terminal fragments, consistent with carboxyl-terminal truncation. The paper does not identify apoE4[Δ(166–299)] or directly compare its molecular weight with those fragments. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • 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 [111]

    The Introduction (page unavailable) says the ApoE isoforms differ at two amino acid positions and describes structural differences and distinct lipid-particle associations. The Discussion and Results (pages unavailable) report isoform-specific interactions with Aβ. They do not establish a strikingly large effect on binding affinities across lipids, Aβ, and receptors; in particular, the paper reports no isoform-specific receptor-binding affinity result. (LLM, conf=0.87)

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Research works printed but not linked: 37

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Authors
Jones, P. B., Adams, K. W., Rozkalne, A., Spires-Jones, T. L., Hshieh, T. T., Hashimoto, T., von Armin, C. A. F., Mielke, M., Bacskai, B. J., & Hyman, B. T.
Affiliations
Harvard University (US)
Corresponding author
Hyman, Bradley T.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2011-01-31
Volume
6
Issue
1
Pages
e14586
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0014586
PMC
PMC3031506
OpenAlex
W2164635944
Cited by
84
References
7
Citations by year
2026: 3 · 2025: 4 · 2024: 5 · 2023: 6 · 2022: 4 · 2021: 5 · 2020: 8 · 2019: 5 · 2018: 3 · 2017: 3 · 2016: 7 · 2015: 3 · 2014: 9 · 2013: 5 · 2012: 10
FWCI
6.11
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (AG005134)
  • National Institute on Aging (AG005134, R01AG026240, P50AG005134, K99AG033670, AG026240)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK048549, R01DK048549)
  • National Institute of Biomedical Imaging and Bioengineering (R01EB000768)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
apolipoprotein E, APOE ε4, APOE3, amyloid-beta, Alzheimer's disease, amyloid plaques, protein-protein interaction, protein conformation, hinge region, FLIM-FRET, in situ measurement, amyloid-beta clearance
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Brain, Female, Humans, Male, Protein Binding, Amyloid beta-Protein Precursor, Protein Structure, Tertiary, Protein Isoforms, Apolipoprotein E3, Apolipoprotein E4, Plaque, Amyloid

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