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Cited by 36Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeurogenesis and neuroplasticity mechanisms

Apolipoprotein E ε4 Mediates Myelin Breakdown by Targeting Oligodendrocytes in Sporadic Alzheimer Disease

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Cheng, Gerald Wai-Yeung, Mok, Kingston King-Shi, Yeung, Sunny Hoi-Sang, Kofler, Julia, Herrup, Karl, Tse, Kai-Hei·2022·Journal of Neuropathology & Experimental Neurology
DOI 10.1093/jnen/nlac054PMC PMC9393713
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Abstract

White matter degradation in the frontal lobe is one of the earliest detectable changes in aging and Alzheimer disease. The ε4 allele of apolipoprotein E (APOE4) is strongly associated with such myelin pathology but the underlying cellular mechanisms remain obscure. We hypothesized that, as a lipid transporter, APOE4 directly triggers pathology in the cholesterol-rich myelin sheath independent of AD pathology. To test this, we performed immunohistochemistry on brain tissues from healthy controls, sporadic, and familial Alzheimer disease subjects. While myelin basic protein expression was largely unchanged, in frontal cortex the number of oligodendrocytes (OLs) was significantly reduced in APOE4 brains independent of their Braak stage or NIA-RI criteria. This high vulnerability of OLs was confirmed in humanized APOE3 or APOE4 transgenic mice. A gradual decline of OL numbers was found in the aging brain without associated neuronal loss. Importantly, the application of lipidated human APOE4, but not APOE3, proteins significantly reduced the formation of myelinating OL in primary cell culture derived from Apoe-knockout mice, especially in cholesterol-depleted conditions. Our findings suggest that the disruption of myelination in APOE4 carriers may represent a direct OL pathology, rather than an indirect consequence of amyloid plaque formation or neuronal loss.

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  • APOE4 is known to disrupt oligodendrocyte differentiation and contribute to myelin breakdown in mouse models without any Alzheimer's disease pathology.

    “APOE4 is known to disrupt oligodendrocyte differentiation and contribute to myelin breakdown in mouse models without any AD pathology. 26 , 27 , 28”

    From Apolipoprotein ε4 exacerbates white matter impairment in a mouse model of Aβ amyloidosis by decreasing actively myelinating oligodendrocytes (2025) · cites this paper as [27]

    The Discussion reports reduced oligodendrocyte numbers in hAPOE4 mice without amyloid plaques, supporting an effect independent of that AD pathology. But the section “Human APOE Depletes OLs, but Not Myelin Fibers in the Aging Mouse Brain” reports unchanged myelinated area, and the Discussion describes impaired maintenance of oligodendrocytes rather than demonstrated disruption of their differentiation in mice. The claim of myelin breakdown in those mice is not supported. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Previous studies using humanized APOE3 and APOE4 mouse models without amyloid pathology revealed inconsistent findings regarding myelination.

    “Previous studies using humanized APOE3 and APOE4 mouse models without amyloid pathology revealed inconsistent findings regarding myelination. One study found no significant difference in myelination, while others observed reduced myelination from electron microscopy images. 27 , 28”

    From Apolipoprotein ε4 exacerbates white matter impairment in a mouse model of Aβ amyloidosis by decreasing actively myelinating oligodendrocytes (2025) · cites this paper as [27]

    In “Human APOE Depletes OLs, but Not Myelin Fibers in the Aging Mouse Brain” (page unavailable), the paper reports no difference in MBP-myelinated area between its humanized APOE3 and APOE4 mice. The Discussion (page unavailable) says these mice produce no amyloid plaques unless crossed with another strain. Our copy does not report the claimed reduced myelination in other mouse studies based on electron microscopy, so it does not establish the claimed inconsistency among previous studies. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • APOE4, but not Braak stages, is highly associated with the loss of oligodendrocyte in frontal cortex of subjects with sporadic or familial Alzheimer's disease.

    “We recently reported APOE4, but not Braak stages, is highly associated with the loss of oligodendrocyte (OL) in frontal cortex of subjects with sAD or familial AD (Cheng et al. 2022).”

    From Apolipoprotein E ε4 disrupts oligodendrocyte differentiation by interfering with astrocyte‐derived lipid transport (2023) · cites this paper as Cheng et al. 2022

  • The APOE4-associated demise of OL population was confirmed in our recent report of human frontal cortex tissues, providing clinical relevance of the impact of APOE4 genotype on OL pathology.

    “The APOE4 associated demise of OLs population was confirmed in our recent report of human frontal cortex tissues which provided clinical relevance of the impact of APOE4 genotype on OL pathology (Cheng et al. 2022).”

    From Apolipoprotein E ε4 disrupts oligodendrocyte differentiation by interfering with astrocyte‐derived lipid transport (2023) · cites this paper as Cheng et al. 2022

  • Post-mortem analysis of brain tissue shows an association between the APOEε4 allele and a reduced number of oligodendrocytes in the frontal cortex after controlling for the severity of AD neuropathology.

    “Post-mortem analysis of brain tissue has shown an association between the APOEε4 allele and a reduced number of oligodendrocytes in the frontal cortex after controlling for the severity of AD neuropathology162.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [162]

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Cited by

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Authors
Cheng, G. W.-Y., Mok, K. K.-S., Yeung, S. H.-S., Kofler, J., Herrup, K., & Tse, K.-H.
Affiliations
  • Hong Kong Polytechnic University (HK)
  • University of Pittsburgh (US)
Corresponding author
Tse, Kai-Hei
ORCID
Venue
Journal of Neuropathology & Experimental Neurology
Publisher
Oxford University Press (OUP)
Published
2022-07-01
Volume
81
Issue
9
Pages
717-730
ISSN
  • 0022-3069 (ISSN-L)
  • 1554-6578
DOI
10.1093/jnen/nlac054
PMC
PMC9393713
OpenAlex
W4283786315
Cited by
36
References
16
Citations by year
2026: 9 · 2025: 11 · 2024: 10 · 2023: 4 · 2022: 2
FWCI
4.18
Type
journal article
Language
en
Open access
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • Journal of Neuropathology & Experimental Neurology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
  • PolyU Institutional Research Archive (Hong Kong Polytechnic University) (submittedVersion)
Funders
  • Research Grant Council, Hong Kong SAR (GRF16124916)
  • Department of Neurobiology, University of Pittsburgh and the Australian National Health and Medical Research Fund (APP1160691)
  • Alzheimer’s Disease Research Center at the University of Pittsburgh
  • National Institute on Aging (P30 AG066468, P50 AG005133)
  • NIA (R01 AG069912)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
APOE ε4, oligodendrocytes, myelin breakdown, sporadic Alzheimer's disease, white matter degeneration, frontal cortex, myelination, cholesterol, brain aging, myelin basic protein, oligodendrocyte loss
MeSH terms
Alzheimer Disease, Animals, Apolipoproteins E, Humans, Mice, Transgenic, Myelin Sheath, Oligodendroglia, Amyloid beta-Peptides, Mice, Apolipoprotein E3, Apolipoprotein E4

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