抑制鞘氨醇激酶 1 可减少鞘氨醇-1-磷酸并加剧淀粉样蛋白-β诱导的混合胶质细胞培养中神经元细胞的死亡

IF 3.2 Q2 CLINICAL NEUROLOGY
Tomoki Minamihata, Katsura Takano-Kawabe, Mitsuaki Moriyama
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引用次数: 0

摘要

在阿尔茨海默病(AD)的病理过程中,老年斑的主要成分淀粉样蛋白-β(Aβ)的积累会激活神经胶质细胞,引起神经炎症。过度的神经炎症会导致神经元脱落,最终产生注意力缺失症的症状。最近的研究表明,鞘氨醇-1-磷酸(S1P)代谢紊乱,尤其是鞘氨醇激酶(SK)1表达减少,继而S1P量减少,可能是AD发病的诱因。因此,我们探讨了 S1P 代谢失调通过改变神经胶质细胞的功能来影响 AD 的可能性。我们评估了SK1药理抑制剂PF-543对脂多糖(LPS)激活的神经胶质细胞、小胶质细胞和星形胶质细胞炎症反应的影响。PF-543 可降低胶质细胞内 S1P 的含量。PF-543 处理增强了经 LPS 处理的神经元/胶质细胞混合培养液中一氧化氮(NO)的产生。此外,我们还发现,在使用星形胶质细胞条件培养基的实验中,PF-543 处理的星形胶质细胞中一氧化氮和活性氧(ROS)产生的增加通过体液因素影响了小胶质细胞的炎症反应。PF-543 处理还减少了小胶质细胞对 Aβ 的摄取,并增加了 Aβ 处理的神经元/胶质细胞混合培养物中受伤神经元的数量。这些结果表明,胶质细胞 S1P 含量的减少会通过改变胶质细胞功能加剧神经炎症和神经退行性变。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Inhibition of Sphingosine Kinase 1 Reduces Sphingosine-1-Phosphate and Exacerbates Amyloid-Beta-Induced Neuronal Cell Death in Mixed-Glial-Cell Culture.

In Alzheimer's disease (AD) pathology, the accumulation of amyloid-beta (Aβ), a main component of senile plaques, activates glial cells and causes neuroinflammation. Excessive neuroinflammation results in neuronal dropouts and finally produces the symptoms of AD. Recent studies suggest that disorder in sphingosine-1-phosphate (S1P) metabolism, especially the decreased expression of sphingosine kinase (SK)1, followed by the reduction in the amount of S1P, can be a promotive factor in AD onset. Thus, we explored the possibility that dysregulated S1P metabolism affects AD through the altered function in glial cells. We evaluated the effect of PF-543, a pharmacological inhibitor of SK1, on the inflammatory responses by lipopolysaccharide (LPS)-activated glial cells, microglia, and astrocytes. The treatment with PF-543 decreased the intracellular S1P content in glial cells. The PF-543 treatment enhanced the nitric oxide (NO) production in the LPS-treated neuron/glia mixed culture. Furthermore, we found that the augmented production of NO and reactive oxygen species (ROS) in the PF-543-treated astrocytes affected the microglial inflammatory responses through humoral factors in the experiment using an astrocyte-conditioned medium. The PF-543 treatment also decreased the microglial Aβ uptake and increased the number of injured neurons in the Aβ-treated neuron/glia mixed culture. These results suggest that a decrease in the glial S1P content can exacerbate neuroinflammation and neurodegeneration through altered glial cell functions.

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来源期刊
Neurology International
Neurology International CLINICAL NEUROLOGY-
CiteScore
3.70
自引率
3.30%
发文量
69
审稿时长
11 weeks
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