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

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. Parkinsonprimes disease (PD) is characterized by the accumulation of alpha-synuclein aggregates (alphaSN-AGs) such as oligomers and fibrils, which contribute to disease progression and severity. Here we study how alphaSN-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 alphaSN-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 alphaSN-AGs. Our work demonstrates the complex relationship between members of the neurovascular unit (NVU) (perivascular astrocytes, neurons, microglia, and endothelial cells), alphaSN-AGs and BBB.