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

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. Parkinsons disease (PD) is characterized by the accumulation of -synuclein aggregates (SN-AGs) such as oligomers and fibrils, which contribute to disease progression and severity. Here we study how SN-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 SN-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 SN-AGs. Our work demonstrates the complex relationship between members of the neurovascular unit (NVU) (perivascular astrocytes, neurons, microglia, and endothelial cells), SN-AGs and BBB. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/504449v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@ab1086org.highwire.dtl.DTLVardef@ca0d5borg.highwire.dtl.DTLVardef@132f39eorg.highwire.dtl.DTLVardef@183ae6_HPS_FORMAT_FIGEXP M_FIG C_FIG