Reconstruction of the human blood–brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes
Name
nihms-1631046.pdf
Description
Accepted version
Size
2.52 MB
Format
Adobe PDF
Checksum (MD5)
404ea020e3553d869d103fbf761ca3cd
Author(s)
Blanchard, Joel W
Bula, Michael
Davila-Velderrain, Jose
Akay, Leyla Anne
Zhu, Lena
Frank, Alexander
Victor, Matheus B
Bonner, Julia Maeve
Mathys, Hansruedi
Lin, Yuan-Ta
Date Issued
2020
Journal
Nature Medicine
Publisher
Springer Science and Business Media LLC
Version
Author's final manuscript
Abstract
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. 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.
MIT Department
Picower Institute for Learning and Memory
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory
Terms of Use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1038/S41591-020-0886-4
