Cited by 150Barrier Structure and Function StudiesDrug Transport and Resistance MechanismsTraumatic Brain Injury and Neurovascular Disturbances

ApoE Deficiency Compromises the Blood Brain Barrier Especially After Injury

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Methia, Nassia, André, Patrick, Hafezi-Moghadam, Ali, Economopoulos, Maria, Thomas, Kennard L., Wagner, Denisa D.·2001·Molecular Medicine

Abstract

BACKGROUND: Apolipoprotein E (apoE) mediates lipoprotein uptake by receptors such as the LDL receptor (LDLR). The isoform apoE4 has been linked to Alzheimer's disease and to poor outcomes after brain injury. Astrocytes that induce blood brain barrier (BBB) properties in endothelium also produce apoE. We decided to investigate the role of apoE in BBB function and in the restoration of BBB after brain injury. MATERIALS AND METHODS: Wild-type (WT) mice and mice deficient in apoE or LDLR were fed normal chow or diets rich in fat and cholesterol. The BBB leakage was determined through injection of Evans blue dye and measurement of the amount of dye extravasated in the brains 3 hours later. Brain injury was induced by applying dry ice directly onto the excised parietal region of the brain. The mice were given 7 days to recover. In some experiments, peroxidase was infused to observe the site of leakage by histology. RESULTS: We found 70% more spontaneous leakage of injected Evans blue dye in the brains of apoE-/- mice than in wild type. This increase in permeability appeared selective for the brain. The leaky BBB in apoE-/- mice may provide an explanation for the neurological deficits seen in these animals. In an established model of BBB leakage induced by trauma (cold injury), the apoE-/- mice showed even more compromised BBB function, compared with WT mice, suggesting that apoE is important for BBB recovery. No deficit in BBB was observed in injured LDLR-/- mice, even on Western Diet. In contrast, higher plasma cholesterol levels in apoE-/- mice further increased BBB leakage after injury. We extracted 5x more Evans blue from these brains than from WT. In the injury model, injection of peroxidase resulted in prominent retention of this protein in the cortex of apoE-/- but not in WT. CONCLUSIONS: Our results show that the combination of loss of apoE function with high plasma cholesterol and especially brain injury results in dramatic BBB defects in the cortex and may explain in part the importance of apoE in Alzheimer's disease and in successful recovery from brain injury.

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  • Transgenic mice lacking Apoe develop an early BBB breakdown.

    “Transgenic mice lacking Apoe also develop an early BBB breakdown (60, 99, 147, 187, 226, 233, 406, 426, 437, 554), indicating that APOE is essential for maintaining BBB integrity.”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [406]

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Authors
Methia, N., André, P., Hafezi-Moghadam, A., Economopoulos, M., Thomas, K. L., & Wagner, D. D.
Affiliations
Harvard University (US)
Corresponding author
Wagner, Denisa D.
Venue
Molecular Medicine
Published
2001-12
Volume
7
Issue
12
Pages
810-815
ISSN
  • 1076-1551 (ISSN-L)
  • 1528-3658
OpenAlex
W1574150981
Cited by
150
References
32
Citations by year
2026: 1 · 2025: 2 · 2024: 6 · 2023: 6 · 2022: 9 · 2021: 7 · 2020: 9 · 2019: 12 · 2018: 7 · 2017: 14 · 2016: 7 · 2015: 10 · 2014: 9 · 2013: 9 · 2012: 6
FWCI
1.01
Type
journal article
Language
en
Open access
Locations
  • Molecular Medicine (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R01-HL-53756, R01HL053756)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
Keywords
apolipoprotein E, blood-brain barrier, blood-brain barrier permeability, brain injury, LDL receptor, serum cholesterol, Western diet, astrocytes, Evans blue leakage, Alzheimer's disease, APOE ε4, BBB repair
MeSH terms
Animals, Apolipoproteins E, Blood-Brain Barrier, Brain Injuries, Capillary Permeability, Cholesterol, Mice, Inbred C57BL, Mice, Knockout, Mice

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