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Cited by 189Alzheimer's disease research and treatmentsCholesterol and Lipid MetabolismNeuroinflammation and Neurodegeneration Mechanisms

ApoE Lipidation as a therapeutic target in Alzheimer’s disease

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Lanfranco, Maria Fe, Ng, Christi Anne, Rebeck, G. William·2020·International Journal of Molecular Sciences
DOI 10.3390/ijms21176336PMC PMC7503657
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Abstract

Apolipoprotein E (APOE) is the major cholesterol carrier in the brain, affecting various normal cellular processes including neuronal growth, repair and remodeling of membranes, synaptogenesis, clearance and degradation of amyloid β (Aβ) and neuroinflammation. In humans, the APOE gene has three common allelic variants, termed E2, E3, and E4. APOE4 is considered the strongest genetic risk factor for Alzheimer’s disease (AD), whereas APOE2 is neuroprotective. To perform its normal functions, apoE must be secreted and properly lipidated, a process influenced by the structural differences associated with apoE isoforms. Here we highlight the importance of lipidated apoE as well as the APOE-lipidation targeted therapeutic approaches that have the potential to correct or prevent neurodegeneration. Many of these approaches have been validated using diverse cellular and animal models. Overall, there is great potential to improve the lipidated state of apoE with the goal of ameliorating APOE-associated central nervous system impairments.

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  • ApoE functionally overlaps with S1P in its involvement in lipid metabolism, neuroinflammatory functions, and related diseases.

    “Because ApoE, a risk factor for AD, functionally overlaps with S1P in its involvement in lipid metabolism, neuroinflammatory functions, and related diseases (46)”

    From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [46]

    Section 6 describes apoE’s role in lipid transport and immunomodulation, and the paper’s opening summary links APOE4 to Alzheimer’s disease and apoE to neuroinflammation. The passages do not establish that apoE functionally overlaps with S1P; searches for S1P and sphingosine-1-phosphate found no such comparison in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • The products of ApoE gene variants differ by only one or two amino acid residues, and these small differences have profound effects on binding to Aβ, ApoE receptors, and lipids.

    “the products of these gene variants differ by only one or two amino acid residues, these small differences have profound effects on binding to Aβ, ApoE receptors, and lipids (46)”

    From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [46]

    The Introduction (section 2; page unavailable) says the three main apoE isoforms differ at residues 112 and 158 and that these substitutions confer different receptor- and lipid-binding abilities. Section 7 discusses ApoE’s role in Aβ clearance and degradation, but the passages found do not establish that the isoforms differ in binding to Aβ. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Brain apoE is primarily produced by glial cells and plays a critical role in lipid transport for neuronal maintenance and repair.

    “Brain apoE is primarily produced by glial cells and plays a critical role in lipid transport for neuronal maintenance and repair”

    From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Lanfranco et al 2020

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Cited by

Sorted by citations

Authors
Lanfranco, M. F., Ng, C. A., & Rebeck, G. W.
Affiliations
Georgetown University Medical Center (US)
Corresponding author
Rebeck, G. William
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2020-09-01
Volume
21
Issue
17
Pages
6336
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms21176336
PMC
PMC7503657
OpenAlex
W3081542127
Cited by
189
References
31
Citations by year
2026: 25 · 2025: 36 · 2024: 43 · 2023: 33 · 2022: 29 · 2021: 22 · 2020: 1
FWCI
2.74
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institutes of Health (R01 NS100704, R01 AG067258)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
apolipoprotein E, Alzheimer's disease, APOE ε4, APOE isoforms, therapeutic target, amyloid-beta clearance, neuroinflammation, cholesterol transport, neurodegeneration, APOE2
MeSH terms
Alzheimer Disease, Animals, Apolipoproteins E, Humans, Lipids, Neuroprotective Agents

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