Monomeric α-synuclein induces blood-brain barrier dysfunction through activated brain pericytes releasing...

Blood-brain barrier (BBB) disruption is often mediated by neuroinflammation, and occurs during various neurodegenerative diseases including Parkinson's disease (PD). PD is characterized by loss of dopaminergic neurons and aggregated α-synuclein protein in inclusions known as Lewy bodies. Misfolded α-synuclein has been implicated in neurodegeneration and neuroinflammation through activation of microglia and astrocytes. Pericytes are a key cellular regulator of the BBB, although it is not known if they participate in α-synuclein-associated PD pathology. Here, we investigated the impact of pericytes on BBB integrity in response to α-synuclein using rat brain endothelial cells (RBECs) co-cultured with rat brain pericytes (RBEC/pericyte co-culture). In RBEC/pericyte co-cultures, α-synuclein added to the abluminal chamber (where pericytes were grown) significantly increased RBEC permeability to sodium fluorescein. In contrast, it had no marked effect when added to the luminal chamber. In the absence of pericytes, both luminal and abluminal addition of α-synuclein failed to affect permeability of the RBEC monolayer. α-Synuclein did not self-assemble in culture media within 24 h, suggesting that monomeric α-synuclein can disrupt the BBB by interacting with pericytes. We found that in response to α-synuclein, pericytes, but not RBECs, released interleukin (IL)-1β, IL-6, monocyte chemotactic protein (MCP)-1, tumor necrosis factor (TNF)-α, and matrix metalloproteinase-9 (MMP-9). α-Synuclein did not affect platelet-derived growth factor (PDGF)-BB release from RBECs and PDGF receptor-β expression in pericytes. These results suggest that pericytes are more sensitive to monomeric α-synuclein than RBECs regarding release of various inflammatory cytokines/chemokines and MMP-9. Thus, monomeric α-synuclein-activated pericytes may contribute to BBB breakdown in patients with PD.