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Cited by 283Barrier Structure and Function StudiesAlzheimer's disease research and treatmentsIntracerebral and Subarachnoid Hemorrhage Research

Reconstruction of the human blood–brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes

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Blanchard, Joel W., Bula, Michael, Davila-Velderrain, Jose, Akay, Leyla Anne, Zhu, Lena, Frank, Alexander, Victor, Matheus B., Bonner, Julia Maeve +7 more·2020·Nature Medicine
DOI 10.1038/s41591-020-0886-4PMC PMC7704032
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Abstract

In Alzheimer's disease, amyloid deposits along the brain vasculature lead to a condition known as cerebral amyloid angiopathy (CAA), which impairs blood-brain barrier (BBB) function and accelerates cognitive degeneration. Apolipoprotein (APOE4) is the strongest risk factor for CAA, yet the mechanisms underlying this genetic susceptibility are unknown. Here we developed an induced pluripotent stem cell-based three-dimensional model that recapitulates anatomical and physiological properties of the human BBB in vitro. Similarly to CAA, our in vitro BBB displayed significantly more amyloid accumulation in APOE4 compared to APOE3. Combinatorial experiments revealed that dysregulation of calcineurin-nuclear factor of activated T cells (NFAT) signaling and APOE in pericyte-like mural cells induces APOE4-associated CAA pathology. In the human brain, APOE and NFAT are selectively dysregulated in pericytes of APOE4 carriers, and inhibition of calcineurin-NFAT signaling reduces APOE4-associated CAA pathology in vitro and in vivo. Our study reveals the role of pericytes in APOE4-mediated CAA and highlights calcineurin-NFAT signaling as a therapeutic target in CAA and Alzheimer's disease.

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  • Recruitment of adaptive immune cells, particularly T and B lymphocytes, can exacerbate neurodegeneration through sustained cytokine production.

    “In parallel, recruitment of adaptive immune cells—particularly T and B lymphocytes—can further exacerbate neurodegeneration through sustained cytokine production despite their initial roles in aggregate clearance [37–41].”

    From Targeted Nanoparticles for Drug Delivery Across the Blood–Brain Barrier in Early and Late Stages of Alzheimer's Disease: A Review (2026) · cites this paper as [41]

    The Discussion (page not available) describes APOE4-related changes in pericytes and vascular amyloid accumulation, not recruitment of T or B lymphocytes. Searches for adaptive immune cells, lymphocyte recruitment, sustained cytokine production, and aggregate clearance found no passage in our copy addressing the attributed mechanism. (LLM, conf=0.76)

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Cited by

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Authors
Blanchard, J. W., Bula, M., Davila-Velderrain, J., Akay, L. A., Zhu, L., Frank, A., Victor, M. B., Bonner, J. M., Mathys, H., Lin, Y.-T., Ko, T., Bennett, D. A., Cam, H. P., Kellis, M., & Tsai, L.-H.
Affiliations
  • Massachusetts Institute of Technology (US)
  • Broad Institute (US)
  • Rush University Medical Center (US)
Corresponding author
Tsai, Li-Huei
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2020-06
Volume
26
Issue
6
Pages
952-963
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-020-0886-4
PMC
PMC7704032
OpenAlex
W3034077561
Cited by
283
References
12
Citations by year
2026: 35 · 2025: 45 · 2024: 36 · 2023: 54 · 2022: 41 · 2021: 53 · 2020: 19
FWCI
15.88
Type
journal article
Language
en
Update notices
correction (2021-01-29)
Open access
Licence
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
Funders
  • Robert A. and Renee E. Belfer Family Foundation
  • Cure Alzheimer’s Fund
  • U.S. Department of Health & Human Services | NIH | National Institute on Aging (AG048056, U54HG008097, UG3NS115064, AG062377, P30AG10161, R01AG15819, R01AG17917)
  • Glenn Family Foundation
  • Howard Hughes Medical Institute (Hannah Gray Postdoctoral Fellowship)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
Keywords
APOE ε4, cerebral amyloid angiopathy, Alzheimer's disease, blood-brain barrier, pericytes, calcineurin/NFAT signaling, amyloid accumulation, APOE3, therapeutic target
MeSH terms
RNA-Seq, Blood-Brain Barrier, Humans, Permeability, Transcription Factors, Amyloid beta-Peptides, Cerebral Amyloid Angiopathy, Calcineurin, Pericytes, NFATC Transcription Factors, Apolipoprotein E3, Apolipoprotein E4, Induced Pluripotent Stem Cells, In Vitro Techniques

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