抑制Kv1.1通道可改善Cu(II)诱导的小鼠小胶质细胞激活和认知障碍。

IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Wenwen Ni, Jiani Ding, Ping Gong, Xiaofang Tan, Juan Li
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引用次数: 0

摘要

小胶质细胞介导的神经炎症在阿尔茨海默病等神经退行性疾病的神经元损伤中起着关键作用。有证据表明电压门控钾通道调节小胶质细胞的激活。我们之前报道过铜稳态失调通过激活小胶质细胞导致神经元损伤。本研究旨在探讨Kv1.1通道在铜诱发的小胶质神经炎症中的作用。用Cu(II)处理BV-2小胶质细胞。DiBAC4(3)测定膜电位。采用酶联免疫吸附试验、Western blotting和免疫染色检测小胶质细胞活化和神经元丢失。采用Morris水迷宫任务评估学习记忆功能。Cu(II)在小胶质细胞中引起超极化膜电位,这一效应被功能性Kv1.1阻断所消除。阻断Kv1.1和用小干扰RNA敲低Kv1.1可抑制Cu(II)诱导的促炎介质的小胶质细胞生成。此外,Kv1.1抑制可减弱Cu(II)刺激的小胶质细胞中PI3K/Akt-ERK1/2信号通路的激活、线粒体活性氧化物质的产生以及核因子-κB的激活。此外,Cu(II)引起的小胶质细胞介导的神经毒性(表现为神经元存活减少和树突损失增加)通过Kv1.1敲除而减弱。在小鼠体内模型中,海马注射Cu(II)导致Kv1.1 mRNA表达升高(但不影响其他Kv1通道),并增强海马小胶质细胞Kv1.1免疫反应性。此外,阻断Kv1.1可减轻Cu(II)诱导的海马小胶质细胞激活和神经元树突损失以及学习和记忆功能障碍。这些发现表明,抑制Kv1.1可改善Cu(II)诱导的小胶质细胞激活和认知障碍。因此,它可能是神经退行性疾病抗炎治疗的潜在分子靶点。
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 Kv1.1 channels ameliorates Cu(II)-induced microglial activation and cognitive impairment in mice.

Microglia-mediated neuroinflammation plays a critical role in neuronal damage in neurodegenerative disorders such as Alzheimer's disease. Evidence shows that voltage-gated potassium (Kv) channels regulate microglial activation. We previously reported that copper dyshomeostasis causes neuronal injury via activating microglia. This study was designed to explore the role of Kv1.1 channels in copper-evoked microglial neuroinflammation. BV-2 microglial cells were treated with Cu(II). DiBAC4(3) was used to measure membrane potential. Microglial activation and neuronal loss were detected by enzyme-linked immunosorbent assay, Western blotting, and immunostaining. Learning and memory function was assessed with Morris water maze task. Cu(II) caused a hyperpolarized membrane potential in microglial cells, an effect abolished by functional Kv1.1 blockade. Blockade of Kv1.1 and knock-down of Kv1.1 with small interfering RNA repressed Cu(II)-induced microglial production of pro-inflammatory mediators. Also, Kv1.1 inhibition attenuated activation of PI3K/Akt-ERK1/2 signaling pathway and production of mitochondrial reactive oxidative species as well as nuclear factor-κB activation in Cu(II)-stimulated microglia. Moreover, the Cu(II)-caused, microglia-mediated neurotoxicity (indicated by reduced neuronal survival and increased dendritic loss) was attenuated by Kv1.1 knock-down. In an in vivo mouse model, hippocampal injection of Cu(II) caused elevated Kv1.1 mRNA (but not other Kv1 channels) expression and enhanced microglial Kv1.1 immunoreactivity in the hippocampus. Furthermore, blockade of Kv1.1 attenuated Cu(II)-induced microglial activation and neuronal dendritic loss in the hippocampus and learning and memory dysfunction. These findings suggest that inhibition of Kv1.1 ameliorates Cu(II)-induced microglial activation and cognitive impairment. Thus, it might represent a potential molecular target for anti-inflammatory therapy of neurodegenerative disorders.

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来源期刊
Neurochemistry international
Neurochemistry international 医学-神经科学
CiteScore
8.40
自引率
2.40%
发文量
128
审稿时长
37 days
期刊介绍: Neurochemistry International is devoted to the rapid publication of outstanding original articles and timely reviews in neurochemistry. Manuscripts on a broad range of topics will be considered, including molecular and cellular neurochemistry, neuropharmacology and genetic aspects of CNS function, neuroimmunology, metabolism as well as the neurochemistry of neurological and psychiatric disorders of the CNS.
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