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Cited by 205Barrier Structure and Function StudiesDrug Transport and Resistance MechanismsAlzheimer's disease research and treatments

APOE4 derived from astrocytes leads to blood–brain barrier impairment

Open access
Jackson, Rosemary J, Meltzer, Jonah C, Nguyen, Huong, Commins, Caitlin, Bennett, Rachel E, Hudry, Eloise, Hyman, Bradley T·2022·Brain
DOI 10.1093/brain/awab478PMC PMC9586546
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Abstract

Apolipoprotein E (ApoE) is a multifaceted secreted molecule synthesized in the CNS by astrocytes and microglia, and in the periphery largely by the liver. ApoE has been shown to impact the integrity of the blood–brain barrier, and, in humans, the APOE4 allele of the gene is reported to lead to a leaky blood–brain barrier. We used allele specific knock-in mice expressing each of the common (human) ApoE alleles, and longitudinal multiphoton intravital microscopy, to directly monitor the impact of various ApoE isoforms on blood–brain barrier integrity. We found that humanized APOE4, but not APOE2 or APOE3, mice show a leaky blood–brain barrier, increased MMP9, impaired tight junctions, and reduced astrocyte end-foot coverage of blood vessels. Removal of astrocyte-produced ApoE4 led to the amelioration of all phenotypes while the removal of astrocyte-produced ApoE3 had no effect on blood–brain barrier integrity. This work shows a cell specific gain of function effect of ApoE4 in the dysfunction of the BBB and implicates astrocyte production of ApoE4, possibly as a function of astrocytic end foot interactions with vessels, as a key regulator of the integrity of the blood–brain barrier.

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Crossref · 10.1093/brain/awab478

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  • Peripheral APOE seems to influence the brain partly by impacting the BBB.

    “peripheral APOE seems to influence the brain partly by impacting the BBB.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [184]

    The Discussion reports that ApoE4 produced by astrocytes impairs BBB integrity, supporting an effect of ApoE on the barrier. It does not establish that peripherally produced ApoE influences the brain through the BBB; the Introduction says the peripheral and brain pools rarely mix. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Compared with wild-type mice, both Apoe knockout mice and mice expressing APOE4 have a leaky BBB, a phenomenon also reported in cognitively unimpaired and mildly impaired individuals who carry an APOEε4 allele.

    “When compared with wild-type mice, both Apoe knockout mice and mice expressing APOE4 have a leaky BBB, a phenomenon also reported in cognitively unimpaired and mildly impaired individuals who carry an APOEε4 allele183–185.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [184]

    The Results (page not available in our copy) report a leaky BBB in Apoe knockout and APOE4 mice, but compare the APOE4 mice with APOE2 and APOE3 mice rather than explicitly with wild-type mice. The Introduction mentions BBB leakage in aged humans with APOE4, but does not specify cognitively unimpaired or mildly impaired individuals. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • APOE4 produced by astrocytes is responsible for BBB leakage.

    “when APOE4 was knocked out from astrocytes, the BBB was able to repair itself, indicating that APOE4 produced by astrocytes is responsible for this BBB leakage184.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [184]

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Research works printed but not linked: 25

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Cited by

Sorted by citations

Authors
Jackson, R. J., Meltzer, J. C., Nguyen, H., Commins, C., Bennett, R. E., Hudry, E., & Hyman, B. T.
Affiliations
  • Harvard University (US)
  • Alzheimer Research Unit, The Massachusetts General Hospital Institute for Neurodegenerative Disease , Charlestown, MA , USA
Corresponding author
Hyman, Bradley T
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2021-12-27
Volume
145
Issue
10
Pages
3582-3593
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awab478
PMC
PMC9586546
OpenAlex
W4200164170
Cited by
205
References
15
Citations by year
2026: 48 · 2025: 62 · 2024: 37 · 2023: 43 · 2022: 15
FWCI
9.48
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Discovery Research Portal (University of Dundee) (publishedVersion, cc-by-nc)
Funders
  • Satter foundation
  • JPB foundation
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
apolipoprotein E, APOE ε4, blood-brain barrier integrity, astrocytes, astrocyte endfeet, tight junctions, MMP-9, APOE isoforms, BBB leakage
MeSH terms
Animals, Astrocytes, Blood-Brain Barrier, Humans, Protein Isoforms, Matrix Metalloproteinase 9, Mice, Apolipoprotein E3, Apolipoprotein E4

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