Cyclophillin A is involved in the uptake of oligomericα-synuclein by brain pericytes

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Parkinson's disease (PD) is characterized by widespread distribution of Lewy bodies, which are mainly composed of aggregated α-synuclein(α-Syn), in the brain. The ability of glial cells to take up extracellular α-Syn contributes to the wide distribution and accumulation of α-Syn in the brain. However, it is unclear whether α-Syn is taken up by brain pericytes, which are a constituent cell of the cerebral microvasculature. We previously found that α-Syn monomer was taken up by brain pericytes. In this study, we investigated the intracellular uptake mechanism in pericytes for more toxic α-Syn oligomers. We used primary cultures of rat brain pericytes. Pericytes took up α-Syn oligomers, and the uptake was decreased at low temperature (4 ℃). After a 1-hr incubation of a-Syn oligomer, the intracellular α-Syn oligomer in pericytes was time-dependently decreased during the next 6 hr. Furthermore, cyclosporin A(CsA), a P-glycoprotein (P-gp) inhibitor, increased the uptake of α-Syn oligomer by pericytes. However, siRNA-mediated knockdown of P-gp failed to increase the uptake of α-Syn oligomers by pericytes. Knockdown of Cyclophillin A (CypA), a molecular target of CsA to inhibit calcineurin activity, decreased the uptake of α-Syn oligomer by pericytes. These results suggested that α-Syn oligomer uptake by pericytes is energy- and CypA-dependent.

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