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Cited by 22Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroscience and Neuropharmacology Research

Opposing Effects of ApoE2 and ApoE4 on Glycolytic Metabolism in Neuronal Aging Supports a Warburg Neuroprotective Cascade against Alzheimer’s Disease

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Zhang, Xin, Wu, Long, Swerdlow, Russell H., Zhao, Liqin·2023·Cells
DOI 10.3390/cells12030410PMC PMC9914046
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Abstract

Apolipoprotein E4 (ApoE4) is the most recognized genetic risk factor for late-onset Alzheimer’s disease (LOAD), whereas ApoE2 reduces the risk for LOAD. The underlying mechanisms are unclear but may include effects on brain energy metabolism. Here, we used neuro-2a (N2a) cells that stably express human ApoE isoforms (N2a-hApoE), differentiated N2a-hApoE neuronal cells, and humanized ApoE knock-in mouse models to investigate relationships among ApoE isoforms, glycolytic metabolism, and neuronal health and aging. ApoE2-expressing cells retained robust hexokinase (HK) expression and glycolytic activity, whereas these endpoints progressively declined with aging in ApoE4-expressing cells. These divergent ApoE2 and ApoE4 effects on glycolysis directly correlated with markers of cellular wellness. Moreover, ApoE4-expressing cells upregulated phosphofructokinase and pyruvate kinase with the apparent intent of compensating for the HK-dependent glycolysis reduction. The introduction of ApoE2 increased HK levels and glycolysis flux in ApoE4 cells. PI3K/Akt signaling was distinctively regulated by ApoE isoforms but was only partially responsible for the ApoE-mediated effects on HK. Collectively, our findings indicate that human ApoE isoforms differentially modulate neuronal glycolysis through HK regulation, with ApoE2 upregulating and ApoE4 downregulating, which markedly impacts neuronal health during aging. These findings lend compelling support to the emerging inverse-Warburg theory of AD and highlight a therapeutic opportunity for bolstering brain glycolytic resilience to prevent and treat AD.

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  • APOE-KO and APOE2 may promote a more robust glycolytic energy profile compared to APOE3 cells.

    “This suggests that APOE-KO and APOE2 may promote a more robust glycolytic energy profile compared to APOE3 cells (Wu et al., 2018; Zhang et al., 2023).”

    From APOE genotype-dependent differences in human astrocytic energy metabolism (2025) · cites this paper as Zhang et al., 2023

    Results §3.3 reports that ApoE2-expressing cells had higher maximum glycolytic capacity than ApoE3-expressing cells at P15, supporting the ApoE2 comparison. The paper does not report an APOE-knockout cell comparison with APOE3, so it does not support that part of the sentence. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • In N2A cells, no glycolytic difference between APOE2, APOE3, and APOE4 cells at an early stage could be observed.

    “In N2A cells, no glycolytic difference between APOE2, -E3, and -E4 cells at an early stage could be observed.”

    From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [28]

  • Many contradictory results on the impact of APOE on energy metabolism have been published.

    “In general, many contradictory results on the impact of APOE on energy metabolism have been published.”

    From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [28]

  • Hexokinase (HK) expression is decreased in APOE4 cells with higher passages, whereas APOE2 and APOE3 showed stable expression of HK over time.

    “This effect could also be observed for hexokinase (HK) expression, which is decreased in APOE4 cells with higher passages, whereas APOE2 and APOE3 showed stable expression of HK over time [28].”

    From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [28]

  • APOE4 has an age-dependent effect on energy metabolism in N2A cells.

    “However, at higher passages, APOE4 N2A cells showed impaired glycolysis and glycolytic activity, indicating an age-dependent effect of APOE4 on their energy metabolism.”

    From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [28]

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Authors
Zhang, X., Wu, L., Swerdlow, R. H., & Zhao, L.
Affiliations
  • University of Kansas (US)
  • University of Kansas Medical Center (US)
Corresponding author
Zhao, Liqin
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2023-01-25
Volume
12
Issue
3
Pages
410
ISSN
2073-4409 (ISSN-L)
DOI
10.3390/cells12030410
PMC
PMC9914046
OpenAlex
W4318054869
Cited by
22
References
13
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en
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  • Cells (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • KU ScholarWorks (University of Kansas) (submittedVersion, cc-by)
Funders
National institutes of Health (R01AG061038, R01AG071682, P30AG072973)
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 › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
apolipoprotein E, APOE2, APOE ε4, Alzheimer's disease, neuronal aging, glycolytic metabolism, hexokinase, Warburg effect, PI3K/Akt signaling, phosphofructokinase, pyruvate kinase, brain energy metabolism, neuroprotection
MeSH terms
Aging, Alzheimer Disease, Animals, Apolipoproteins E, Glycolysis, Humans, Phosphatidylinositol 3-Kinases, Protein Isoforms, Mice, 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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