Transfer of neuron-derived ?-synuclein to astrocytes induces neuroinflammation and blood-brain barrier damage after methamphetamine exposure: Involving the regulation of nuclear receptor-associated protein 1
Transfer of neuron-derived ?-synuclein to astrocytes induces neuroinflammation and blood-brain barrier damage after methamphetamine exposure: Involving the regulation of nuclear receptor-associated protein 1
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DOI：
10.1016/j.bbi.2022.09.002
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发表时间：
2022-11-01
影响因子：
15.1
通讯作者：
Qiu，Pingming
中科院分区：
文献类型：
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作者：
Huang，Jian;Ding，Jiuyang;Qiu，Pingming
α-突触核蛋白(α-SYN)参与了甲基苯丙胺(METH)诱导的神经毒性。神经元可以将过量的α-SYN转移到邻近的神经元和神经胶质细胞。冰毒暴露后星形胶质细胞中α-SYN聚集对血脑屏障的影响尚不清楚。我们先前的研究表明，核受体相关蛋白1(NURR1)是广泛表达于脑内的核受体家族成员，参与了冰毒诱导的α-SYN在星形胶质细胞内积聚从而激活神经炎症的过程。Nurr1在星形胶质细胞介导的神经炎症中所起的作用尚不清楚，而星形胶质细胞介导的神经炎症导致冰毒诱导的BBB损伤。本研究发现，甲硫氨酸通过上调神经元α-SYN的表达延伸至星形胶质细胞，从而激活星形胶质细胞，通过下调NURR1的表达，提高和降低IL-1β、IL-6、肿瘤坏死因子-α和胶质细胞源性神经营养因子的水平，最终损伤血脑屏障。具体地说，血脑屏障对伊文思蓝和荧光素钠(NaF)的通透性增加；脑实质中Ig G沉积增加；Claudin5、occludin和PDGFFRβ水平降低。血脑屏障内可见脑微血管管径异常、星形胶质细胞末端足肿胀、周细胞覆盖率降低、紧密连接缺失等超微结构改变。然而，敲除或抑制α-SYN或星形胶质细胞特异性过表达的Nurr1部分缓解了这些症状和血脑屏障损伤。此外，体外实验证实，冰毒可增加原代培养神经元中α-SYN的水平，并可进一步转移到原代培养的星形胶质细胞中，导致NURR1水平下降。NURR1水平降低可导致脑微血管内皮细胞IL-1β、IL-6、肿瘤坏死因子-α水平升高，胶质细胞源性神经营养因子水平降低，从而改变原代培养的脑微血管内皮细胞对NaF的通透性、跨内皮电阻、Claudin 5和occludin水平。基于我们的发现，我们提出了一种新的机制来阐明冰毒引起的血脑屏障损伤，并提出了α-SYN和NURR1作为有希望的药物干预靶点来减少冰毒滥用者的血脑屏障损伤和由此产生的神经毒性。
The α-synuclein (α-syn) is involved in methamphetamine (METH)-induced neurotoxicity. Neurons can transfer excessive α-syn to neighboring neurons and glial cells. The effects of α-syn aggregation in astrocytes after METH exposure on the blood–brain barrier (BBB) remains unclear. Our previous study demonstrated that nuclear receptor-related protein 1 (Nurr1), a member of the nuclear receptor family widely expressed in the brain, was involved in the process of METH-induced α-syn accumulated in astrocytes to activate neuroinflammation. The role Nurr1 plays in astrocyte-mediated neuroinflammation, which results in BBB injury induced by METH, remains uncertain. This study found that METH up-regulated α-syn expression in neurons extended to astrocytes, thereby eliciting astrocyte activation, increasing and decreasing IL-1β, IL-6, TNF-α, and GDNF levels by down-regulating Nurr1 expression, and ultimately damaging the BBB. Specifically, the permeability of BBB to Evans blue and sodium fluorescein (NaF) increased; IgG deposits in the brain parenchyma increased; the Claudin5, Occludin, and PDGFRβ levels decreased. Several ultrastructural pathological changes occurred in the BBB, such as abnormal cerebral microvascular diameter, astrocyte end-foot swelling, decreased pericyte coverage, and loss of tight junctions. However, knockout or inhibition of α-syn or astrocyte-specific overexpression of Nurr1 partially alleviated these symptoms and BBB injury. Moreover, thein vitroexperiments confirmed that METH increased α-syn level in the primary cultured neurons, which could be further transferred to primary cultured astrocytes, resulting in decreased Nurr1 levels. The decreased Nurr1 levels mediated the increase of IL-1β, IL-6, and TNF-α, and the decrease of GDNF, thereby changing the permeability to NaF, transendothelial electrical resistance, and Claudin5 and Occludin levels of primary cultured brain microvascular endothelial cells. Based on our findings, we proposed a new mechanism to elucidate METH-induced BBB injury and presented α-syn and Nurr1 as promising drug intervention targets to reduce BBB injury and resulting neurotoxicity in METH abusers.