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Cited by 82Neuroinflammation and Neurodegeneration MechanismsMultiple Sclerosis Research StudiesNeurological Disease Mechanisms and Treatments

Opposing effects of apoE2 and apoE4 on microglial activation and lipid metabolism in response to demyelination

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Wang, Na, Wang, Minghui, Jeevaratnam, Suren, Rosenberg, Cassandra, Ikezu, Tadafumi C., Shue, Francis, Doss, Sydney V., Alnobani, Alla +6 more·2022·Molecular Neurodegeneration
DOI 10.1186/s13024-022-00577-1PMC PMC9682675
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Abstract

Background: Abnormal lipid accumulation has been recognized as a key element of immune dysregulation in microglia whose dysfunction contributes to neurodegenerative diseases. Microglia play essential roles in the clearance of lipid-rich cellular debris upon myelin damage or demyelination, a common pathogenic event in neuronal disorders. Apolipoprotein E (apoE) plays a pivotal role in brain lipid homeostasis; however, the apoE isoform-dependent mechanisms regulating microglial response upon demyelination remain unclear. Methods: To determine how apoE isoforms impact microglial response to myelin damage, 2-month-old apoE2-, apoE3-, and apoE4-targeted replacement (TR) mice were fed with normal diet (CTL) or 0.2% cuprizone (CPZ) diet for four weeks to induce demyelination in the brain. To examine the effects on subsequent remyelination, the cuprizone diet was switched back to regular chow for an additional two weeks. After treatment, brains were collected and subjected to immunohistochemical and biochemical analyses to assess the myelination status, microglial responses, and their capacity for myelin debris clearance. Bulk RNA sequencing was performed on the corpus callosum (CC) to address the molecular mechanisms underpinning apoE-mediated microglial activation upon demyelination. Results: We demonstrate dramatic isoform-dependent differences in the activation and function of microglia upon cuprizone-induced demyelination. ApoE2 microglia were hyperactive and more efficient in clearing lipid-rich myelin debris, whereas apoE4 microglia displayed a less activated phenotype with reduced clearance efficiency, compared with apoE3 microglia. Transcriptomic profiling revealed that key molecules known to modulate microglial functions had differential expression patterns in an apoE isoform-dependent manner. Importantly, apoE4 microglia had excessive buildup of lipid droplets, consistent with an impairment in lipid metabolism, whereas apoE2 microglia displayed a superior ability to metabolize myelin enriched lipids. Further, apoE2-TR mice had a greater extent of remyelination; whereas remyelination was compromised in apoE4-TR mice. Conclusions: Our findings provide critical mechanistic insights into how apoE isoforms differentially regulate microglial function and the maintenance of myelin dynamics, which may inform novel therapeutic avenues for targeting microglial dysfunctions in neurodegenerative diseases.

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  • E2 expression decreases microgliosis compared to E3 and E4.

    “decrease microgliosis”

    From Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement (2027) · cites this paper as Wang et al., 2022

    The Results section, “Microgliosis is dramatically increased in apoE2-TR mice,” reports the opposite: after cuprizone-induced demyelination, apoE2 mice had a larger increase in Iba1+ microglia than apoE4 mice, and higher Iba1 protein levels than both apoE3 and apoE4 mice. (LLM, conf=0.95)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • E2 expression upregulates genes associated with cellular migration and the immune response in microglia compared to E3 and E4.

    “upregulate genes associated with cellular migration and the immune response in microglia compared to E3 and E4”

    From Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement (2027) · cites this paper as Wang et al., 2022

    The Results section (page not available in our copy) reports that migration- and immune-response-related genes were more highly upregulated in apoE2-TR mice than in apoE3-TR or apoE4-TR mice. The comparison was made after cuprizone-induced demyelination; the claim omits that condition and thus implies a broader effect than the paper establishes. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • APOE is a lipid transporter expressed in astrocytes and microglia and affects microglial functions including neuroinflammation and phagocytosis.

    “APOE is a lipid transporter expressed in astrocytes and microglia and has been shown to affect microglial functions including neuroinflammation and phagocytosis7–9.”

    From The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway (2025) · cites this paper as [8]

  • APOE is a lipid transporter expressed on astrocytes and microglia and affects numerous microglial functions including neuroinflammation and phagocytosis.

    “APOE is a lipid transporter expressed on astrocytes and microglia and has been shown to affect numerous microglial functions including neuroinflammation and phagocytosis8–10.”

    From <i>APOE3</i> - <i>R136S</i> mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition (2024) · cites this paper as [9]

  • E2 expression increases phagocytic activity in microglia compared to E3 and E4.

    “E2 expression has been shown to increase phagocytic activity”

    From Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement (2027) · cites this paper as Wang et al., 2022

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Authors
Wang, N., Wang, M., Jeevaratnam, S., Rosenberg, C., Ikezu, T. C., Shue, F., Doss, S. V., Alnobani, A., Martens, Y. A., Wren, M., Asmann, Y. W., Zhang, B., Bu, G., & Liu, C.-C.
Affiliations
  • Mayo Clinic (US)
  • Icahn School of Medicine at Mount Sinai (US)
Corresponding author
  • Bu, Guojun
  • Liu, Chia-Chen
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2022-11-23
Volume
17
Issue
1
Pages
75-75
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-022-00577-1
PMC
PMC9682675
OpenAlex
W4309838288
Cited by
82
References
39
Citations by year
2026: 23 · 2025: 24 · 2024: 25 · 2023: 10
FWCI
5.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
Funders
  • NIH Blueprint for Neuroscience Research (AG062110, U19AG069701, RF1AG046205, R37AG027924)
  • Cure Alzheimer's Fund
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
apolipoprotein E isoforms, APOE2, APOE ε4, microglial activation, demyelination, cuprizone, remyelination, myelin debris clearance, lipid metabolism, lipid droplets, microglial transcriptome, neurodegenerative diseases
MeSH terms
Animals, Apolipoproteins E, Cuprizone, Demyelinating Diseases, Microglia, Lipid Metabolism, Mice, Apolipoprotein E3, Apolipoprotein E4, Apolipoprotein E2

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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