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

Nature Medicine
Joel W BlanchardLi-Huei Tsai

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.

References

Mar 26, 2004·Transplantation Proceedings·M H KapturczakB Kaplan
Apr 6, 2005·Trends in Neurosciences·Berislav V Zlokovic
Jun 21, 2005·Cellular and Molecular Neurobiology·Máiria A DeliMasami Niwa
May 12, 2006·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Qin XuYadong Huang
Oct 24, 2009·Journal of Vascular Research·Anthony Wayne OrrBrian R Wamhoff
Oct 15, 2010·Nature·Annika ArmulikChrister Betsholtz
Dec 2, 2010·Current Neuropharmacology·Francesca BonominiRita Rezzani
Aug 16, 2011·Developmental Cell·Annika ArmulikChrister Betsholtz
Dec 14, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Jungsu KimDavid M Holtzman
Jan 11, 2012·Nature Reviews. Neurology·Philip Scheltens, Jeroen D C Goos
Jan 27, 2012·Nature·Mason A IsraelLawrence S B Goldstein
Jun 2, 2012·Current Neuropharmacology·Lindsay C Reese, Giulio Taglialatela
Oct 30, 2012·Bioinformatics·Alexander DobinThomas R Gingeras
Nov 26, 2013·Neuron·Costantino Iadecola
Feb 11, 2014·Methods in Molecular Biology·Amin BoroujerdiRichard Milner
Sep 5, 2014·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Ye ZhangJian Qian Wu
Jan 15, 2015·Journal of Laboratory Automation·Balaji SrinivasanJames J Hickman
Jan 18, 2015·Brain : a Journal of Neurology·Prashanthi VemuriClifford R Jack
Mar 19, 2015·Annual Review of Neuroscience·Benjamin J AndreoneChenghua Gu
Jul 28, 2015·Nature Cell Biology·Christoph PatschChad A Cowan
Sep 25, 2015·Journal of Alzheimer's Disease : JAD·Giulio TaglialatelaLuca Cicalese
Oct 8, 2015·Trends in Neurosciences·Brian Wai Chow, Chenghua Gu
Nov 23, 2015·Cell·Zhen ZhaoBerislav V Zlokovic
Dec 15, 2015·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·David AttwellTurgay Dalkara
May 18, 2016·Acta Neuropathologica·Mitsuru ShinoharaTakahisa Kanekiyo
Aug 20, 2016·Science·Richard M Ransohoff
Nov 4, 2016·Scientific Reports·Jyoti GautamYao Yao
Feb 15, 2018·Nature·Michael VanlandewijckChrister Betsholtz
Apr 26, 2018·Genes & Development·Natasha M O'BrownChenghua Gu
Jun 6, 2018·Journal of Alzheimer's Disease : JAD·David A BennettJulie A Schneider
Jun 28, 2018·Proceedings of the National Academy of Sciences of the United States of America·Jingshu WangNancy R Zhang

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Citations

Aug 21, 2020·Journal of Neuroscience Research·Anindita BhattacharyaV Wee Yong
Jul 8, 2020·International Journal of Molecular Sciences·Olga Bondareva, Bilal N Sheikh
Sep 22, 2020·Current Protocols in Stem Cell Biology·Antje Appelt-MenzelOle Pless
Oct 6, 2020·Epilepsy Currents·Vanesa Nieto-Estévez, Jenny Hsieh
Jun 24, 2020·Tissue Engineering. Part B, Reviews·Richard JeskeYan Li
Jun 28, 2020·Nature Reviews. Neuroscience·Sian Lewis
Oct 13, 2020·Frontiers in Immunology·Kyle KasparianEiron Cudaback
Oct 21, 2020·Fluids and Barriers of the CNS·Ethan S LippmannEric V Shusta
Dec 20, 2020·Lancet Neurology·Alberto Serrano-PozoBradley T Hyman
Jan 12, 2021·Molecular Therapy : the Journal of the American Society of Gene Therapy·Gabriella MacDougallOrnit Chiba-Falek
Oct 8, 2020·Cell Reports·Priyanka NarayanSusan Lindquist
Feb 10, 2021·Neurochemical Research·Marloes VerkerkeJinte Middeldorp
Jan 24, 2021·Current Protocols·Benjamin D GastfriendSean P Palecek
Mar 25, 2021·APL Bioengineering·Callie M Weber, Alisa Morss Clyne
Apr 6, 2021·Neural Regeneration Research·Tara M CaffreyJerome Robert
Apr 4, 2021·Ageing Research Reviews·Brittani R PriceChristopher M Norris
Dec 2, 2020·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Yuanming LiJinhao Sun
May 1, 2021·Micromachines·Tiffany CameronKaren C Cheung
May 1, 2021·Stem Cell Research & Therapy·Elena Coccia, Tim Ahfeldt
Apr 20, 2021·Frontiers in Cell and Developmental Biology·Haroon KhanGuo-Yuan Yang
Jun 3, 2021·Advanced Healthcare Materials·Jeong-Kee YoonYongTae Kim
Jun 13, 2021·Journal of Molecular and Cellular Cardiology·Christian J MandryckyYing Zheng
Jul 25, 2021·International Journal of Molecular Sciences·Ying-Chieh WuŠárka Lehtonen
Jul 14, 2021·Annual Review of Biomedical Engineering·Cynthia HajalBen M Maoz
Jul 31, 2021·The American Journal of Pathology·Tessa V ProcterAxel Montagne
Aug 10, 2021·Nature Aging·William A BanksMichelle A Erickson
Nov 26, 2021·Neuropathology and Applied Neurobiology·Carolin KurzRobert Perneczky

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Methods Mentioned

BETA
RNA-seq
PCR
BECs
SMA
snRNA-seq
ELISA
GTPase

Software Mentioned

feature Counts
Cuffdiff
IMARIS
STAR
ACTIONet

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