Transfer of pathological α-synuclein from neurons to astrocytes via exosomes causes inflammatory responses after METH exposure
Transfer of pathological α-synuclein from neurons to astrocytes via exosomes causes inflammatory responses after METH exposure
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DOI：
10.1016/j.toxlet.2020.06.016
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发表时间：
2020-10-01
影响因子：
3.5
通讯作者：
Qiu, Pingming
中科院分区：
文献类型：
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作者：
Meng, Yunle;Ding, Jiuyang;Qiu, Pingming
甲基苯丙胺是一种高度成瘾性的精神兴奋剂，滥用会导致许多健康并发症。我们之前的研究表明，甲基安非他明暴露会增加α -突触核蛋白（α -syn）的表达。最近有研究表明，α -syn可以通过外泌体从神经元转移到星形胶质细胞。然而，星形胶质细胞在甲基苯丙胺神经毒性相关的α -syn病理中的具体作用尚不清楚。本研究的目的是确定meth处理神经元的外泌体是否含有病理α -syn，并验证外泌体可以将病理α -syn从神经元转移到星形胶质细胞的假设。为此，通过动物和细胞系共培养模型，研究人员发现，从甲基甲氧嘧啶处理的SH-SY5Y细胞中分离的外泌体含有病理性α -syn。此外，在原代培养的星形胶质细胞培养基中加入甲基安非他明外泌体可诱导星形胶质细胞a-syn聚集和炎症反应。然后，我们评估了暴露于甲基甲氧胺或α -syn的原代培养星形胶质细胞中核受体相关1蛋白（Nurr1）表达和炎症细胞因子水平的变化。我们发现甲基甲氧基甲基化或α -syn暴露降低了Nurr1的表达，增加了星形胶质细胞中促炎细胞因子的表达。我们的研究结果表明，α -syn可以通过外泌体从神经元细胞转移到星形胶质细胞。当内化的α -syn在星形胶质细胞中积累时，细胞产生炎症反应。Nurrl可能在这一过程中起着至关重要的作用，可能是甲基安非他明引起的炎症损伤的治疗靶点。
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.