ApoE (Apolipoprotein E) in brain pericytes regulates endothelial function in an isoform-dependent manner by modulating basement membrane components
Open accessAbstract
Objective: The ε4 allele of the APOE gene ( APOE4 ) is the strongest genetic risk factor for Alzheimer disease when compared with the common ε3 allele. Although there has been significant progress in understanding how apoE4 (apolipoprotein E4) drives amyloid pathology, its effects on amyloid-independent pathways, in particular cerebrovascular integrity and function, are less clear. Approach and Results: Here, we show that brain pericytes, the mural cells of the capillary walls, differentially modulate endothelial cell phenotype in an apoE isoform-dependent manner. Extracellular matrix protein induction, tube-like structure formation, and barrier formation were lower with endothelial cells cocultured with pericytes isolated from apoE4-targeted replacement (TR) mice compared with those from apoE3-TR mice. Importantly, aged apoE4-targeted replacement mice had decreased extracellular matrix protein expression and increased plasma protein leakages compared with apoE3-TR mice. Conclusions: ApoE4 impairs pericyte-mediated basement membrane formation, potentially contributing to the cerebrovascular effects of apoE4.
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Astrocytes are the major producers of cerebral ApoE, which plays a relevant role in Aβ clearance.
“Notably, astrocytes are the major producers of cerebral ApoE [64], which has been reported to play a relevant role in Aβ clearance [63].”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [63]
The Results (Characterization of primary brain pericytes; page unavailable) report that cultured mouse astrocytes secreted roughly three to four times as much ApoE as pericytes, while endothelial cells secreted less. This supports astrocytes as substantial ApoE producers, but the comparison of cultured cells does not establish that they are the major producers of cerebral ApoE overall. The Aβ-clearance statement is attributed to a different citation, [63], and is not judged here. (LLM, conf=0.81)
Experimental — accuracy not yet measuredPericytes isolated from APOE3-targeted replacement (TR) mice support greater endothelial barrier integrity and tube-like structure formation than APOE4 pericytes.
“Pericytes isolated from APOE3-targeted replacement (TR) mice support greater endothelial barrier integrity and tube-like structure formation than APOE4 pericytes (Yamazaki et al., 2020).”
From APOE3-Christchurch variant enhances neurovascular support functions of iPSC-derived mesenchymal stromal cells (2026) · cites this paper as Yamazaki et al., 2020
APOE3 has been considered neutral with regard to AD risk.
“In contrast to APOE4, which has been related to higher risk and younger age of AD onset, APOE3 has been considered neutral with regard to AD risk [63].”
From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [63]
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Endothelial Cell APOE3 Regulates Neurovascular, Neuronal, and Behavioral Function
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APOE Genotype and Endothelial Biomarkers: Towards Personalized Cardiovascular Screening
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Pericytes and the Neurovascular Unit: The Critical Nexus of Alzheimer Disease Pathogenesis?
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Comprehensive behavioral study of C57BL/6.KOR-ApoEshl mice
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Self-citationApoE, Atherosclerosis, and Hypercholesterolemia
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APOE, Biomarkers, and Proteogenomics in Alzheimer’s Disease
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APOE-ε4 links CD8+ T cell infiltration to white matter inflammation in Alzheimer’s disease
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- Authors
- Yamazaki, Y., Shinohara, M., Yamazaki, A., Ren, Y., Asmann, Y. W., Kanekiyo, T., & Bu, G.
- Affiliations
- Mayo Clinic (US)
- Mayo Clinic in Florida (US)
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2020-01
- Volume
- 40
- Issue
- 1
- Pages
- 128-144
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- PMC
- PMC7007705
- OpenAlex
- W2982766098
- Cited by
- 89
- References
- 52
- Citations by year
- 2026: 16 · 2025: 14 · 2024: 10 · 2023: 22 · 2022: 8 · 2021: 9 · 2020: 9 · 2019: 1
- FWCI
- 2.97
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- National Institute on Aging (RF1AG051504, R01AG051574, R01AG027924, R37AG027924, RF1AG057181, RF1AG046205, R01AG046205, R01AG035355, P30AG062677, P50AG016574)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- apolipoprotein E, APOE ε4, APOE3, brain pericytes, endothelial cells, endothelial function, basement membrane, extracellular matrix, cerebrovascular integrity, plasma protein leakage, Alzheimer's disease, APOE isoforms, targeted replacement mice, aging
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Basement Membrane, Brain, Cells, Cultured, Disease Models, Animal, Endothelium, Vascular, Enzyme-Linked Immunosorbent Assay, Female, Gene Expression Regulation, Humans, Male, Mice, Inbred C57BL, Protein Isoforms, Pericytes, Mice
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