Transfer of pathological alpha-synuclein from neurons to astrocytes via exosomes causes inflammatory responses after METH exposure

Methamphetamine (METH) is a highly addictive psychostimulant drug whose abuse can cause many health complications. Our previous studies have shown that METH exposure increases alpha-synuclein (alpha-syn) expression. Recently, it was shown that alpha-syn could be transferred from neurons to astrocytes via exosomes. However, the specific role of astrocytes in alpha-syn pathology involved in METH neurotoxicity remains unclear. The objective of this study was to determine whether exosomes derived from METH-treated neurons contain pathological alpha-syn and test the hypothesis that exosomes can transfer pathological alpha-syn from neurons to astrocytes. To this end, using animal and cell line coculture models, we show that exosomes isolated from METH-treated SH-SY5Y cells contained pathological alpha-syn. Furthermore, the addition of METH exosomes to the medium of primary cultured astrocytes induced a-syn aggregation and inflammatory responses in astrocytes. Then, we evaluated changes in nuclear receptor related 1 protein (Nurr1) expression and the levels of inflammatory cytokines in primary cultured astrocytes exposed to METH or alpha-syn. We found that METH or alpha-syn exposure decreased Nurr1 expression and increased proinflammatory cytokine expression in astrocytes. Our results indicate that alpha-syn can be transferred from neuronal cells to astrocytes through exosomes. When internalized alpha-syn accumulated in astrocytes, the cells produced inflammatory responses. Nurrl may play a crucial role in this process and could be a therapeutic target for inflammatory damage caused by METH.