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The impact of α-synuclein aggregates on blood-brain barrier integrity in the presence of neurovascular unit cells

Hamdam Hourfar, Farhang Aliakbari, Shabboo Rahimi Aqdam, Zahra Nayeri, Hassan Bardania, Daniel E. Otzen, Dina Morshedi
doi: https://doi.org/10.1101/2022.08.18.504449
Hamdam Hourfar
aBioprocess Engineering Research Group, Department of Industrial and Environmental Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
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Farhang Aliakbari
aBioprocess Engineering Research Group, Department of Industrial and Environmental Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
bMolecular Medicine Research Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
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Shabboo Rahimi Aqdam
cDepartment of Neuroscience, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
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Zahra Nayeri
aBioprocess Engineering Research Group, Department of Industrial and Environmental Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
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Hassan Bardania
dCellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
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Daniel E. Otzen
eInterdisciplinary Nanoscience Centre (iNANO), Aarhus University, Aarhus C, Denmark
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Dina Morshedi
aBioprocess Engineering Research Group, Department of Industrial and Environmental Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
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  • For correspondence: morshedi@nigeb.ac.ir
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Abstract

The role of the blood-brain barrier (BBB) is to control trafficking of biomolecules and protect the brain. This function can be compromised by pathological conditions. Parkinson’s disease (PD) is characterized by the accumulation of α-synuclein aggregates (αSN-AGs) such as oligomers and fibrils, which contribute to disease progression and severity. Here we study how αSN-AGs affect the BBB in in vitro co-culturing models consisting of human brain endothelial hCMEC/D3 cells alone and co-cultured with astrocytes and neurons/glial cells. When cultivated on their own, hCMEC/D3 cells were compromised by αSN-AGs, which decreased cellular viability, mitochondrial membrane potential, wound healing activity, TEER and permeability parameters, as well as increased the levels of ROS and NO. Co-culturing of these cells with activated microglia also increased BBB impairment according to TEER and systemic immune cell transmigration assays. In contrast, hCMEC/D3 cells co-cultured with astrocytes or dopaminergic neurons or simultaneously treated with their conditioned media showed increased resistance against αSN-AGs. Our work demonstrates the complex relationship between members of the neurovascular unit (NVU) (perivascular astrocytes, neurons, microglia, and endothelial cells), αSN-AGs and BBB.

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Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 19, 2022.
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The impact of α-synuclein aggregates on blood-brain barrier integrity in the presence of neurovascular unit cells
Hamdam Hourfar, Farhang Aliakbari, Shabboo Rahimi Aqdam, Zahra Nayeri, Hassan Bardania, Daniel E. Otzen, Dina Morshedi
bioRxiv 2022.08.18.504449; doi: https://doi.org/10.1101/2022.08.18.504449
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The impact of α-synuclein aggregates on blood-brain barrier integrity in the presence of neurovascular unit cells
Hamdam Hourfar, Farhang Aliakbari, Shabboo Rahimi Aqdam, Zahra Nayeri, Hassan Bardania, Daniel E. Otzen, Dina Morshedi
bioRxiv 2022.08.18.504449; doi: https://doi.org/10.1101/2022.08.18.504449

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