Enhancing the Astrocytic Clearance of Extracellular α-Synuclein Aggregates by Ginkgolides Attenuates Neural Cell Injury

The accumulation of aggregated forms of the alpha-Synuclein (alpha-Syn) is associated with the pathogenesis of Parkinson's disease (PD), and the efficient clearance of aggregated alpha-Syn represents a potential approach in PD therapy. Astrocytes are the most numerous glia cells in the brain and play an essential role in supporting brain functions in PD state. In the present study, we demonstrated that cultured primary astrocytes engulfed and degraded extracellular aggregated recombinant human alpha-Syn. Meanwhile, we observed that the clearance of alpha-Syn by astrocytes was abolished by proteasome inhibitor MG132 and autophagy inhibitor 3-methyladenine (3MA). We further showed that intracellular alpha-Syn was reduced after ginkgolide B (GB) and bilobalide (BB) treatment, and the decrease was reversed by MG132 and 3MA. More importantly, GB and BB reduced indirect neurotoxicity to neurons induced by alpha-Syn-stimulated astrocytic conditioned medium. Together, we firstly find that astrocytes can engulf and degrade alpha-Syn aggregates via the proteasome and autophagy pathways, and further show that GB and BB enhance astrocytic clearance of alpha-Syn, which gives us an insight into the novel therapy for PD in future.