NADPH oxidase as a therapeutic target in Alzheimer's disease.
NADPH oxidase as a therapeutic target in Alzheimer's disease.
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DOI：
10.1186/1471-2202-9-s2-s8
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发表时间：
2008-12-03
期刊：
影响因子：
2.4
通讯作者：
Block, Michelle L.
中科院分区：
文献类型：
--
作者：
Block, Michelle L.
目前，阿尔茨海默病（AD）的可用治疗方法在很大程度上无法阻止疾病进展。小胶质细胞是大脑中的常驻巨噬细胞，与AD的病理学和渐进性变性性质密切相关。具体而言，小胶质细胞响应于β淀粉样蛋白（Aβ）和神经元损伤而被激活，并且可以成为神经毒性细胞因子和活性氧（ROS）的慢性来源。NADPH氧化酶是一种多亚基酶复合物，负责小胶质细胞产生细胞外和细胞内ROS。重要的是，AD中NADPH氧化酶表达上调，是小胶质细胞介导的Aβ神经毒性的重要组成部分。小胶质细胞NADPH氧化酶的激活通过两种机制引起神经毒性：1）小胶质细胞产生的细胞外ROS对神经元直接有毒; 2）细胞内ROS在小胶质细胞中作为信号传导机制发挥作用，以放大几种促炎和神经毒性细胞因子（例如，肿瘤坏死因子-α、前列腺素E2和白细胞介素-1 β）的产生。以下综述描述了靶向NADPH氧化酶如何减少广谱毒性因子（例如，细胞因子、ROS和活性氮），从而抑制有害小胶质细胞活化（Aβ和神经元损伤）的两个触发因素引起的神经元损伤，为阻止AD进展提供了希望。
At present, available treatments for Alzheimer's disease (AD) are largely unable to halt disease progression. Microglia, the resident macrophages in the brain, are strongly implicated in the pathology and progressively degenerative nature of AD. Specifically, microglia are activated in response to both β amyloid (Aβ) and neuronal damage, and can become a chronic source of neurotoxic cytokines and reactive oxygen species (ROS). NADPH oxidase is a multi-subunit enzyme complex responsible for the production of both extracellular and intracellular ROS by microglia. Importantly, NADPH oxidase expression is upregulated in AD and is an essential component of microglia-mediated Aβ neurotoxicity. Activation of microglial NADPH oxidase causes neurotoxicity through two mechanisms: 1) extracellular ROS produced by microglia are directly toxic to neurons; 2) intracellular ROS function as a signaling mechanism in microglia to amplify the production of several pro-inflammatory and neurotoxic cytokines (for example, tumor necrosis factor-α, prostaglandin E2, and interleukin-1β). The following review describes how targeting NADPH oxidase can reduce a broad spectrum of toxic factors (for example, cytokines, ROS, and reactive nitrogen species) to result in inhibition of neuronal damage from two triggers of deleterious microglial activation (Aβ and neuron damage), offering hope in halting the progression of AD.