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The role of mutations associated with familial neurodegenerative disorders on blood–brain barrier function in an iPSC model

BACKGROUND: Blood–brain barrier dysfunction is associated with many late-stage neurodegenerative diseases. An emerging question is whether the mutations associated with neurodegenerative diseases can independently lead to blood–brain barrier (BBB) dysfunction. Studies from patient-derived induced pl...

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Autores principales: Katt, Moriah E., Mayo, Lakyn N., Ellis, Shannon E., Mahairaki, Vasiliki, Rothstein, Jeffrey D., Cheng, Linzhao, Searson, Peter C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628493/
https://www.ncbi.nlm.nih.gov/pubmed/31303172
http://dx.doi.org/10.1186/s12987-019-0139-4
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author Katt, Moriah E.
Mayo, Lakyn N.
Ellis, Shannon E.
Mahairaki, Vasiliki
Rothstein, Jeffrey D.
Cheng, Linzhao
Searson, Peter C.
author_facet Katt, Moriah E.
Mayo, Lakyn N.
Ellis, Shannon E.
Mahairaki, Vasiliki
Rothstein, Jeffrey D.
Cheng, Linzhao
Searson, Peter C.
author_sort Katt, Moriah E.
collection PubMed
description BACKGROUND: Blood–brain barrier dysfunction is associated with many late-stage neurodegenerative diseases. An emerging question is whether the mutations associated with neurodegenerative diseases can independently lead to blood–brain barrier (BBB) dysfunction. Studies from patient-derived induced pluripotent stem cells suggest that mutations associated with neurodegenerative disease are non-cell autonomous, resulting in gain of toxic function in derived neurons and astrocytes. Here we assess whether selected mutations associated with neurodegenerative diseases can contribute to impairment of the blood–brain barrier. METHODS: We assessed barrier function of confluent monolayers of human brain microvascular endothelial cells (hBMECs) derived from induced pluripotent stem cells (iPSC) from three healthy individuals and eight individuals with neurodegenerative disease. We systematically assessed protein and gene expression of BBB biomarkers, transendothelial resistance (TEER), permeability of Lucifer yellow, permeability of d-glucose, permeability of rhodamine 123, the efflux ratio of rhodamine 123, and P-gp inhibition using Tariquidar for confluent monolayers of human brain microvascular endothelial cell (hBMECs). RESULTS: We provide evidence supporting the hypothesis that mutations associated with neurodegenerative disease can independently cause BBB dysfunction. These functional changes are not catastrophic since barrier breakdown would result in BBB impairment during development. Synergistic interactions between non-cell autonomous cerebrovascular dysfunction and the effects of gain-of-toxic function in neurons (e.g. toxic oligomers) are likely to increase disease burden through a positive feedback mechanism. CONCLUSIONS: These results suggest that the accumulation of defects in brain microvascular endothelial cells may ultimately lead to impairment of the BBB. Small changes in barrier function over time could lead to accumulated defects that result in positive feedback to unrelated central nervous system diseases. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12987-019-0139-4) contains supplementary material, which is available to authorized users.
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spelling pubmed-66284932019-07-23 The role of mutations associated with familial neurodegenerative disorders on blood–brain barrier function in an iPSC model Katt, Moriah E. Mayo, Lakyn N. Ellis, Shannon E. Mahairaki, Vasiliki Rothstein, Jeffrey D. Cheng, Linzhao Searson, Peter C. Fluids Barriers CNS Research BACKGROUND: Blood–brain barrier dysfunction is associated with many late-stage neurodegenerative diseases. An emerging question is whether the mutations associated with neurodegenerative diseases can independently lead to blood–brain barrier (BBB) dysfunction. Studies from patient-derived induced pluripotent stem cells suggest that mutations associated with neurodegenerative disease are non-cell autonomous, resulting in gain of toxic function in derived neurons and astrocytes. Here we assess whether selected mutations associated with neurodegenerative diseases can contribute to impairment of the blood–brain barrier. METHODS: We assessed barrier function of confluent monolayers of human brain microvascular endothelial cells (hBMECs) derived from induced pluripotent stem cells (iPSC) from three healthy individuals and eight individuals with neurodegenerative disease. We systematically assessed protein and gene expression of BBB biomarkers, transendothelial resistance (TEER), permeability of Lucifer yellow, permeability of d-glucose, permeability of rhodamine 123, the efflux ratio of rhodamine 123, and P-gp inhibition using Tariquidar for confluent monolayers of human brain microvascular endothelial cell (hBMECs). RESULTS: We provide evidence supporting the hypothesis that mutations associated with neurodegenerative disease can independently cause BBB dysfunction. These functional changes are not catastrophic since barrier breakdown would result in BBB impairment during development. Synergistic interactions between non-cell autonomous cerebrovascular dysfunction and the effects of gain-of-toxic function in neurons (e.g. toxic oligomers) are likely to increase disease burden through a positive feedback mechanism. CONCLUSIONS: These results suggest that the accumulation of defects in brain microvascular endothelial cells may ultimately lead to impairment of the BBB. Small changes in barrier function over time could lead to accumulated defects that result in positive feedback to unrelated central nervous system diseases. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12987-019-0139-4) contains supplementary material, which is available to authorized users. BioMed Central 2019-07-15 /pmc/articles/PMC6628493/ /pubmed/31303172 http://dx.doi.org/10.1186/s12987-019-0139-4 Text en © The Author(s) 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Katt, Moriah E.
Mayo, Lakyn N.
Ellis, Shannon E.
Mahairaki, Vasiliki
Rothstein, Jeffrey D.
Cheng, Linzhao
Searson, Peter C.
The role of mutations associated with familial neurodegenerative disorders on blood–brain barrier function in an iPSC model
title The role of mutations associated with familial neurodegenerative disorders on blood–brain barrier function in an iPSC model
title_full The role of mutations associated with familial neurodegenerative disorders on blood–brain barrier function in an iPSC model
title_fullStr The role of mutations associated with familial neurodegenerative disorders on blood–brain barrier function in an iPSC model
title_full_unstemmed The role of mutations associated with familial neurodegenerative disorders on blood–brain barrier function in an iPSC model
title_short The role of mutations associated with familial neurodegenerative disorders on blood–brain barrier function in an iPSC model
title_sort role of mutations associated with familial neurodegenerative disorders on blood–brain barrier function in an ipsc model
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628493/
https://www.ncbi.nlm.nih.gov/pubmed/31303172
http://dx.doi.org/10.1186/s12987-019-0139-4
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