Early administration of galantamine from preplaque phase suppresses oxidative stress and improves cognitive behavior in APPswe/PS1dE9 mouse model of Alzheimer's disease
Early administration of galantamine from preplaque phase suppresses oxidative stress and improves cognitive behavior in APPswe/PS1dE9 mouse model of Alzheimer's disease
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DOI：
10.1016/j.freeradbiomed.2019.09.014
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发表时间：
2019-12-01
影响因子：
7.4
通讯作者：
Shimohama, Shun
中科院分区：
文献类型：
--
作者：
Saito, Taro;Hisahara, Shin;Shimohama, Shun
阿尔茨海默病(AD)是一种常见的神经退行性疾病，会逐渐损害记忆和认知。淀粉样β蛋白(Aβ)沉积是阿尔茨海默病最重要的病理生理标志。活性氧自由基(ROS)的产生引起的氧化应激是AD中的一种突出现象，已知发生在AD的早期。一些报告表明氧化还原状态的改变与AD病理之间的关系，包括进行性Aβ沉积、神经胶质细胞激活和炎症。加兰他明是一种乙酰胆碱酯酶抑制剂，已有报道具有氧化应激抑制功能。在本研究中，从Aβ斑块出现之前(斑块前阶段)开始给AD模型小鼠口服加兰他明，并使用电子顺磁共振(EPR)成像技术测量体内脑组织氧化还原状态的变化。斑块前期给予加兰他明可改善Morris水迷宫实验和新物体识别实验中的记忆衰退。用EPR成像监测大脑的氧化还原状态表明，加兰他明治疗改善了不平衡的氧化还原状态。此外，加兰他明增强了小胶质细胞的功能，促进了Aβ的清除，减少了皮质中Aβ阳性区域和大脑中不溶性Aβ的数量。相反，斑块前阶段的加兰他明治疗通过神经毒性小胶质细胞活动抑制了促炎细胞因子的产生。因此，从斑块前期开始给药可能具有预防AD的临床应用潜力。此外，我们的结果证明了EPR成像在快速和定量评估疾病修饰药物对AD的疗效方面的有效性。
Alzheimer's disease (AD) is a common neurodegenerative disease that progressively impairs memory and cognition. Deposition of amyloid-beta (A beta) peptides is the most important pathophysiological hallmark of AD. Oxidative stress induced by generation of reactive oxygen species (ROS) is a prominent phenomenon in AD and known to occur early in the course of AD. Several reports suggest a relationship between change in redox status and AD pathology including progressive A beta deposition, glial cell activation, and inflammation. Galantamine is an acetylcholinesterase inhibitor and has been reported to have an oxidative stress inhibitory function. In the present study, galantamine was administered orally to AD model mice from before the appearance of A beta plaques (preplaque phase), and in vivo change in redox status of the brain was measured using electron paramagnetic resonance (EPR) imaging. Administration of galantamine from the preplaque phase ameliorated memory decline in Morris water maze test and novel object recognition test. Monitoring of the redox status of the brain using EPR imaging showed that galantamine treatment improved the unbalanced redox state. Additionally, galantamine administration enhanced microglial function to promote A beta clearance, reducing the A beta-positive area in the cortex and amount of insoluble A beta in the brain. In contrast, galantamine treatment from the preplaque phase suppressed the production of proinflammatory cytokines through neurotoxic microglial activity. Therefore, galantamine administration from the preplaque phase may have the potential of clinical application for the prevention of AD. In addition, our results demonstrate the usefulness of EPR imaging for speedy and quantitative evaluation of the efficacy of disease-modifying drugs for AD.