C9ORF72 patient-derived endothelial cells drive blood-brain barrier disruption and contribute to neurotoxicity

Abstract

The blood-brain barrier (BBB) serves as a highly intricate and dynamic interface connecting the brain and the bloodstream, playing a vital role in maintaining brain homeostasis. BBB dysfunction has been associated with multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS); however, the role of the BBB in neurodegeneration is understudied. We developed an ALS patient-derived model of the BBB by using cells derived from 5 patient donors carrying C9ORF72 mutations. Brain microvascular endothelial-like cells (BMEC-like cells) derived from C9ORF72-ALS patients showed altered gene expression, compromised barrier integrity, and increased P-glycoprotein transporter activity. In addition, mitochondrial metabolic tests demonstrated that C9ORF72-ALS BMECs display a significant decrease in basal glycolysis accompanied by increased basal and ATP-linked respiration. Moreover, our study reveals that C9-ALS derived astrocytes can further affect BMECs function and affect the expression of the glucose transporter Glut-1. Finally, C9ORF72 patient-derived BMECs form leaky barriers through a cell-autonomous mechanism and have neurotoxic properties towards motor neurons.

Metadata

Item Type:	Article
Authors/Creators:	Aragón-González, A. Shaw, A.C. https://orcid.org/0000-0002-7321-7994 Kok, J.R. Roussel, F.S. Santos Souza, C.D. Granger, S.M. Vetter, T. de Diego, Y. Meyer, K.C. Beal, S.N. Shaw, P.J. Ferraiuolo, L.
Copyright, Publisher and Additional Information:	© 2024 The Author(s). Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data.
Keywords:	Stem cells; Blood brain barrier; Amyotrophic lateral sclerosis; C9ORF72; In vitro modelling; Neurodegeneration
Dates:	Published: December 2024 Published (online): 11 April 2024 Accepted: 2 March 2024 Submitted: 18 December 2023
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Neuroscience (Sheffield)
Depositing User:	Symplectic Sheffield
Date Deposited:	15 Apr 2024 15:12
Last Modified:	15 Apr 2024 15:12
Status:	Published
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1186/s12987-024-00528-6
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:211512

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C9ORF72 patient-derived endothelial cells drive blood-brain barrier disruption and contribute to neurotoxicity

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