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

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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.

Original languageEnglish
JournalInternational Journal of Biological Macromolecules
Pages (from-to)305-320
Number of pages16
Publication statusPublished - Feb 2023


  • Blood-brain barrier
  • Neurovascular unit
  • α-Synuclein aggregates


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