Regional microglia are transcriptionally distinct but similarly exacerbate neurodegeneration in a culture model of Parkinson's disease.
Regional microglia are transcriptionally distinct but similarly exacerbate neurodegeneration in a culture model of Parkinson's disease.
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DOI：
10.1186/s12974-018-1181-x
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发表时间：
2018-05-11
影响因子：
9.3
通讯作者：
Iacovitti L
中科院分区：
文献类型：
--
作者：
Kostuk EW;Cai J;Iacovitti L
帕金森病（Parkinson's disease，PD）是一种以黑质腹侧被盖区（Ventral tegmental area，VTA）多巴胺能神经元的选择性变性为特征的疾病。VTA的选择性保护和SN的易感性的潜在机制仍然是未知的。在这里，我们证明了星形胶质细胞和小胶质细胞之间的平衡在SN DA神经元的PD模拟毒素1-甲基-4-苯基吡啶（MPP+）的敏感性的重要性。以前建立的方法被用来分离星形胶质细胞和小胶质细胞从皮质（CTX），SN，和VTA，以及胚胎中脑DA神经元从SN和VTA。通过qRT-PCR在有和没有MPP+暴露的情况下检查分离的小胶质细胞的21种典型促炎和抗炎细胞因子的转录谱。建立了神经元和星形胶质细胞的同型和异型共培养物，并研究了改变体外星形胶质细胞和小胶质细胞的比例对中脑DA神经元对PD模拟毒素MPP+的敏感性的影响。我们发现，区域分离的小胶质细胞（SN，VTA，CTX）表现出其细胞因子谱的基础差异，这些小胶质细胞与MPP+的激活导致差异细胞因子上调。向SN神经元和星形胶质细胞培养物中添加小胶质细胞不足以引起神经变性;然而，当用MPP+激发时，所有区域分离的小胶质细胞导致MPP+毒性加重，其通过抑制小胶质细胞活化而缓解。此外，我们证明，孤立的腹侧被盖区，但不是SN，星形胶质细胞能够介导的SN和腹侧被盖区DA神经元的保护，即使在存在恶化的小胶质细胞，但是，这种保护可以逆转增加的小胶质细胞的数量。这些结果表明，中脑内星形胶质细胞和小胶质细胞的平衡是PD发病机制中所见的SN DA神经元的选择性脆弱性的关键因素，并且VTA星形胶质细胞介导DA神经元的保护，这可以被更多数量的有害小胶质细胞抵消。本文的在线版本（10.1186/s12974-018-1181-x）包含补充材料，可供授权用户使用。
Parkinson’s disease (PD) is characterized by selective degeneration of dopaminergic (DA) neurons of the substantia nigra pars compacta (SN) while neighboring ventral tegmental area (VTA) DA neurons are relatively spared. Mechanisms underlying the selective protection of the VTA and susceptibility of the SN are still mostly unknown. Here, we demonstrate the importance of balance between astrocytes and microglia in the susceptibility of SN DA neurons to the PD mimetic toxin 1-methyl-4-phenylpyridinium (MPP+). Previously established methods were used to isolate astrocytes and microglia from the cortex (CTX), SN, and VTA, as well as embryonic midbrain DA neurons from the SN and VTA. The transcriptional profile of isolated microglia was examined for 21 canonical pro- and anti-inflammatory cytokines by qRT-PCR with and without MPP+ exposure. Homo- and heterotypic co-cultures of neurons and astrocytes were established, and the effect of altering the ratio of astrocytes and microglia in vitro on the susceptibility of midbrain DA neurons to the PD mimetic toxin MPP+ was investigated. We found that regionally isolated microglia (SN, VTA, CTX) exhibit basal differences in their cytokine profiles and that activation of these microglia with MPP+ results in differential cytokine upregulation. The addition of microglia to cultures of SN neurons and astrocytes was not sufficient to cause neurodegeneration; however, when challenged with MPP+, all regionally isolated microglia resulted in exacerbation of MPP+ toxicity which was alleviated by inhibition of microglial activation. Furthermore, we demonstrated that isolated VTA, but not SN, astrocytes were able to mediate protection of both SN and VTA DA neurons even in the presence of exacerbatory microglia; however, this protection could be reversed by increasing the numbers of microglia present. These results suggest that the balance of astrocytes and microglia within the midbrain is a key factor underlying the selective vulnerability of SN DA neurons seen in PD pathogenesis and that VTA astrocytes mediate protection of DA neurons which can be countered by greater numbers of deleterious microglia. The online version of this article (10.1186/s12974-018-1181-x) contains supplementary material, which is available to authorized users.
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影响因子：
12.8
作者：
Lee, He-Jin;Cho, Eun-Duk;Lee, Kyung Won;Kim, Jung-Hyun;Cho, Ssang-Goo;Lee, Seung-Jae
通讯作者：
Lee, Seung-Jae
影响因子：
3.3
作者：
APPEL, K;HONEGGER, P;GEBICKEHAERTER, PJ
通讯作者：
GEBICKEHAERTER, PJ
DOI：
10.1124/jpet.102.035048
发表时间：
2003-01-01
影响因子：
3.5
作者：
Liu, B;Hong, JS
通讯作者：
Hong, JS
影响因子：
5.3
作者：
Lian, Hong;Litvinchuk, Alexandra;Zheng, Hui
通讯作者：
Zheng, Hui
影响因子：
5.3
作者：
Gao, HM;Hong, JS;Liu, B
通讯作者：
Liu, B