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

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  • Hamdam Hourfar, National Institute for Biotechnology and Genetic Engineering
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  • Farhang Aliakbari, National Institute for Biotechnology and Genetic Engineering, Western University
  • ,
  • Shabboo Rahimi Aqdam, University of Calgary
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  • Zahra Nayeri, National Institute for Biotechnology and Genetic Engineering
  • ,
  • Hassan Bardania, Yasuj University of Medical Sciences
  • ,
  • Daniel E Otzen
  • Dina Morshedi, National Institute for Biotechnology and Genetic Engineering

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 (to overcome inter-species differences) 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 value, and enhanced permeability, 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.

TidsskriftInternational Journal of Biological Macromolecules
Sider (fra-til)305-320
Antal sider16
StatusUdgivet - feb. 2023

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