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Differences in Recycling of Apolipoprotein E3 and E4—LDL Receptor Complexes—A Mechanistic Hypothesis

Kim, Meewhi, Bezprozvanny, Ilya·2021·International Journal of Molecular Sciences
DOI 10.3390/ijms22095030PMC PMC8126166
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Abstract

Apolipoprotein E (ApoE) is a protein that plays an important role in the transport of fatty acids and cholesterol and in cellular signaling. On the surface of the cells, ApoE lipoparticles bind to low density lipoprotein receptors (LDLR) that mediate the uptake of the lipids and downstream signaling events. There are three alleles of the human ApoE gene. Presence of ApoE4 allele is a major risk factor for developing Alzheimer’s disease (AD) and other disorders late in life, but the mechanisms responsible for biological differences between different ApoE isoforms are not well understood. We here propose that the differences between ApoE isoforms can be explained by differences in the pH-dependence of the association between ApoE3 and ApoE4 isoforms and LDL-A repeats of LDLR. As a result, the following endocytosis ApoE3-associated LDLRs are recycled back to the plasma membrane but ApoE4-containing LDLR complexes are trapped in late endosomes and targeted for degradation. The proposed mechanism is predicted to lead to a reduction in steady-state surface levels of LDLRs and impaired cellular signaling in ApoE4-expressing cells. We hope that this proposal will stimulate experimental research in this direction that allows the testing of our hypothesis.

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  • ApoE4 is able to reduce recycling of the three receptors to the cell membrane, likely because of aberrant endosomal acidification that traps receptors within intracellular compartments and leads to their degradation.

    “several studies showed that ApoE4 is able to reduce their recycling to the cell membrane, likely because of the aberrant endosomal acidification that traps receptors within the intracellular compartments and leads to their degradation [73,74,75].”

    From ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis (2022) · cites this paper as [74]

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Metadata

Authors
Kim, M., & Bezprozvanny, I.
Affiliations
Department of Physiology, UT Southwestern Medical Center, Dallas, TX 75390, USA
ORCID
Bezprozvanny, Ilya
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2021-05-10
Volume
22
Issue
9
Pages
5030
ISSN
1422-0067
DOI
10.3390/ijms22095030
PMC
PMC8126166
Cited by
11
References
12
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • National Institute of Neurological Disorders and Stroke (R01NS056224)
  • National Institute on Aging (R01AG055577)
  • Russian Science Foundation (19-15-00184)

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