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

Publisher: Biomed Central Country of Publication: England NLM ID: 101553157 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-8118 (Electronic) Linking ISSN: 20458118 NLM ISO Abbreviation: Fluids Barriers CNS Subsets: MEDLINE

Original Publication: London : Biomed Central

Amyotrophic Lateral Sclerosis*/genetics ; Blood-Brain Barrier*/metabolism ; Endothelial Cells*/metabolism; Humans ; C9orf72 Protein/genetics ; C9orf72 Protein/metabolism

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.
(© 2024. The Author(s).)

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765704 Horizon 2020

Keywords: In vitro modelling; Amyotrophic lateral sclerosis; Blood brain barrier; C9ORF72; Neurodegeneration; Stem cells

0 (C9orf72 Protein)

Date Created: 20240411 Date Completed: 20240415 Latest Revision: 20240429

20240429

PMC11007886

10.1186/s12987-024-00528-6

38605366