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首页> 外文期刊>Frontiers in Neuropharmacology >The Potassium Channel KCa3.1 Represents a Valid Pharmacological Target for Astrogliosis-Induced Neuronal Impairment in a Mouse Model of Alzheimer’s Disease
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The Potassium Channel KCa3.1 Represents a Valid Pharmacological Target for Astrogliosis-Induced Neuronal Impairment in a Mouse Model of Alzheimer’s Disease

机译：钾通道KCa3.1代表阿尔茨海默氏病小鼠模型中由星形胶质瘤引起的神经元受损的有效药理学目标

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Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive decline of cognitive function. Astrogliosis plays a critical role in AD by instigating neuroinflammation, which leads ultimately to cognition decline. We previously showed that the intermediate-conductance Ca2+-activated potassium channel (KCa3.1) is involved in astrogliosis induced by TGF-β in vitro. In the present study, we investigated the contribution of KCa3.1 channels to astrogliosis-mediated neuroinflammation, using TgAPP/PS1 mice as a model for AD. We found that KCa3.1 expression was increased in reactive astrocytes as well as in neurons in the brains of both TgAPP/PS1 mice and AD patients. Pharmacological blockade of KCa3.1 significantly reduced astrogliosis, microglial activation, neuronal loss and memory deficits. KCa3.1 blockade inhibited astrocyte activation and reduced brain levels of IL-1β, TNF-α, iNOS and COX-2. Furthermore, we used primary co-cultures of cortical neurons and astrocytes to demonstrate an important role for KCa3.1 in the process of astrogliosis-induced neuroinflammatory responses during amyloid-β (Aβ)-induced neuronal loss. KCa3.1 was found to be involved in the Aβ-induced activated biochemical profile of reactive astrocytes, which included activation of JNK MAPK and production of reactive oxygen species (ROS). Pharmacological blockade of KCa3.1 attenuated Aβ-induced reactive astrocytes and indirect, astrogliosis-mediated damage to neurons. Our data clearly indicate a role for astrogliosis in AD pathogenesis and suggest that KCa3.1 inhibition might represent a good therapeutic target for the treatment of AD.
机译：阿尔茨海默氏病（AD）是一种神经退行性疾病，其特征是认知功能逐渐下降。星形胶质沉着症通过刺激神经炎症在AD中起关键作用，最终导致认知能力下降。我们先前显示，中导Ca2 +激活的钾通道（KCa3.1）在体外参与了由TGF-β诱导的星形胶质变。在本研究中，我们使用TgAPP / PS1小鼠作为AD模型，调查了KCa3.1通道对星形胶质瘤介导的神经炎症的贡献。我们发现，在TgAPP / PS1小鼠和AD患者的大脑中，反应性星形胶质细胞和神经元中的KCa3.1表达均增加。 KCa3.1的药理学阻断作用显着减少了星形胶质细胞增多症，小胶质细胞活化，神经元丢失和记忆缺陷。 KCa3.1阻断剂抑制星形胶质细胞活化并降低脑中IL-1β，TNF-α，iNOS和COX-2的水平。此外，我们使用皮质神经元和星形胶质细胞的初级共培养来证明KCa3.1在淀粉样β（Aβ）诱导的神经元丧失过程中，星形胶质化诱导的神经炎症反应的过程中起重要作用。发现KCa3.1参与Aβ诱导的反应性星形胶质细胞活化生化特征，包括JNK MAPK的活化和活性氧（ROS）的产生。 KCa3.1的药理阻断作用减弱了Aβ诱导的反应性星形胶质细胞和星形胶质细胞介导的对神经元的间接损伤。我们的数据清楚地表明了星形胶质细胞增生在AD发病机理中的作用，并表明KCa3.1抑制可能代表了AD的良好治疗靶标。

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