Apolipoprotein E Regulates the Integrity of Tight Junctions in an Isoform-dependent Manner in an in Vitro Blood-Brain Barrier Model
Open accessAbstract
Apolipoprotein E (apoE) is a major apolipoprotein in the brain. The ε4 allele of apoE is a major risk factor for Alzheimer disease, and apoE deficiency in mice leads to blood-brain barrier (BBB) leakage. However, the effect of apoE isoforms on BBB properties are as yet unknown. Here, using an in vitro BBB model consisting of brain endothelial cells and pericytes prepared from wild-type (WT) mice, and primary astrocytes prepared from human apoE3- and apoE4-knock-in mice, we show that the barrier function of tight junctions (TJs) was impaired when the BBB was reconstituted with primary astrocytes from apoE4-knock-in mice (apoE4-BBB model). The phosphorylation of occludin at Thr residues and the activation of protein kinase C (PKC)η in mBECs were attenuated in the apoE4-BBB model compared with those in the apoE3-BBB model. The differential effects of apoE isoforms on the activation of PKCη, the phosphorylation of occludin at Thr residues, and TJ integrity were abolished following the treatment with an anti-low density lipoprotein receptor-related protein 1 (LRP1) antibody or a LRP1 antagonist receptor-associated protein. Consistent with the results of in vitro studies, BBB permeability was higher in apoE4-knock-in mice than in apoE3-knock-in mice. Our studies provide evidence that TJ integrity in BBB is regulated by apoE in an isoform-dependent manner.
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Transgenic mice expressing human APOE4 gene, but not APOE3 and APOE2, develop an early BBB breakdown, cerebral microhemorrhages, and loss of endothelial GLUT1 expression that is followed by secondary neurodegenerative changes.
“Transgenic mice expressing human APOE4 gene, but not APOE3 and APOE 2, develop an early BBB breakdown (60, 437), cerebral microhemorrhages (85), and loss of endothelial GLUT1 expression (9) that is followed by secondary neurodegenerative changes (60).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [437]
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 [437]
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- Authors
- Nishitsuji, K., Hosono, T., Nakamura, T., Bu, G., & Michikawa, M.
- Affiliations
- National Center for Geriatrics and Gerontology (JP)
- Mayo Clinic (US)
- Corresponding author
- Michikawa, Makoto
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-05
- Volume
- 286
- Issue
- 20
- Pages
- 17536-17542
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3093828
- OpenAlex
- W1998494497
- Cited by
- 275
- References
- 16
- Citations by year
- 2026: 18 · 2025: 16 · 2024: 27 · 2023: 16 · 2022: 14 · 2021: 20 · 2020: 26 · 2019: 24 · 2018: 11 · 2017: 21 · 2016: 20 · 2015: 22 · 2014: 15 · 2013: 14 · 2012: 9
- FWCI
- 7.08
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- National Center for Geriatrics and Gerontology (21-11)
- National Institutes of Health
- Japan Society for the Promotion of Science (19300138, 21300145)
- National Institute on Aging (P01AG030128, R01AG027924, R01AG035355)
- 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 isoforms, APOE ε4, tight junction integrity, blood-brain barrier, brain endothelial cells, pericytes, astrocytes, occludin phosphorylation, protein kinase C eta, LRP1, receptor-associated protein, blood-brain barrier permeability, Alzheimer's disease risk
- MeSH terms
- Alzheimer Disease, Animals, Astrocytes, Blood-Brain Barrier, Cells, Cultured, Enzyme Activation, Humans, Membrane Proteins, Models, Biological, Permeability, Phosphorylation, Protein Kinase C, Receptors, LDL, Antigens, CD, Mice, Knockout, Tight Junctions, Protein Isoforms, Pericytes, Tumor Suppressor Proteins, Low Density Lipoprotein Receptor-Related Protein-1, Endothelial Cells, Mice, Apolipoprotein E3, Apolipoprotein E4, Gene Knock-In Techniques, Occludin
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