The role of mutations associated with familial neurodegenerative disorders on blood–brain barrier function in an iPSC model
Open Access
- 15 July 2019
- journal article
- research article
- Published by Springer Science and Business Media LLC in Fluids and Barriers of the CNS
- Vol. 16 (1), 1-13
- https://doi.org/10.1186/s12987-019-0139-4
Abstract
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. 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). 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. 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.Keywords
Funding Information
- Defense Threat Reduction Agency (HDTRA1-15-1-0046)
This publication has 80 references indexed in Scilit:
- Derivation of blood-brain barrier endothelial cells from human pluripotent stem cellsNature Biotechnology, 2012
- Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerabilityProceedings of the National Academy of Sciences of the United States of America, 2012
- Efficient human iPS cell derivation by a non-integrating plasmid from blood cells with unique epigenetic and gene expression signaturesCell Research, 2011
- Menadione triggers cell death through ROS-dependent mechanisms involving PARP activation without requiring apoptosisFree Radical Biology & Medicine, 2010
- Prion-like mechanisms in neurodegenerative diseasesNature Reviews Neuroscience, 2009
- Genomewide association study for susceptibility genes contributing to familial Parkinson diseaseHuman Genetics, 2008
- ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degenerationNature Neuroscience, 2008
- Altered morphology and 3D architecture of brain vasculature in a mouse model for Alzheimer's diseaseProceedings of the National Academy of Sciences of the United States of America, 2008
- Decreased blood–brain barrier P-glycoprotein function in the progression of Parkinson’s disease, PSP and MSAJournal of Neural Transmission, 2008
- Protein aggregation and neurodegenerative diseaseNature Medicine, 2004