BACKGROUND Alzheimer's disease (AD) is a major clinical problem, but there is a distinct lack of effective therapeutic drugs for this disease. We investigated the potential therapeutic effects of zerumbone, a subtropical ginger sesquiterpene, in transgenic APP/PS1 mice, rodent models of AD which exhibit cerebral amyloidosis and neuroinflammation. METHODS The N9 microglial cell line and primary microglial cells were cultured to investigate the effects of zerumbone on microglia. APP/PS1 mice were treated with zerumbone, and non-cognitive and cognitive behavioral impairments were assessed and compared between the treatment and control groups. The animals were then sacrificed, and tissues were collected for further analysis. The potential therapeutic mechanism of zerumbone and the signaling pathways involved were also investigated by RT-PCR, western blot, nitric oxide detection, enzyme-linked immunosorbent assay, immunohistochemistry, immunofluorescence, and flow cytometry analysis. RESULTS Zerumbone suppressed the expression of pro-inflammatory cytokines and induced a switch in microglial phenotype from the classic inflammatory phenotype to the alternative anti-inflammatory phenotype by inhibiting the mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B signaling pathway in vitro. After a treatment period of 20 days, zerumbone significantly ameliorated deficits in both non-cognitive and cognitive behaviors in transgenic APP/PS1 mice. Zerumbone significantly reduced β-amyloid deposition and attenuated pro-inflammatory microglial activation in the cortex and hippocampus. Interestingly, zerumbone significantly increased the proportion of anti-inflammatory microglia among all activated microglia, potentially contributing to reduced β-amyloid deposition by enhancing phagocytosis. Meanwhile, zerumbone also reduced the expression of key molecules of the MAPK pathway, such as p38 and extracellular signal-regulated kinase. CONCLUSIONS Overall, zerumbone effectively ameliorated behavioral impairments, attenuated neuroinflammation, and reduced β-amyloid deposition in transgenic APP/PS1 mice. Zerumbone exhibited substantial anti-inflammatory activity in microglial cells and induced a phenotypic switch in microglia from the pro-inflammatory phenotype to the anti-inflammatory phenotype by inhibiting the MAPK signaling pathway, which may play an important role in its neuroprotective effects. Our results suggest that zerumbone is a potential therapeutic agent for human neuroinflammatory and neurodegenerative diseases, in particular AD.

中文翻译：

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Zerumbone通过抑制MAPK信号传导改善了转基因APP / PS1小鼠的行为障碍和神经病理学。

背景技术阿尔茨海默氏病（AD）是主要的临床问题，但是明显缺乏用于该疾病的有效治疗药物。我们研究了亚热带姜倍半萜酮，蛇菊酮在转基因APP / PS1小鼠，AD啮齿动物模型中的潜在治疗作用，该模型表现出脑淀粉样变性和神经炎症。方法培养N9小胶质细胞系和原代小胶质细胞，以研究蛇骨素对小胶质细胞的影响。APP / PS1小鼠接受了um骨治疗，评估了非认知和认知行为障碍，并在治疗组和对照组之间进行了比较。然后处死动物，并收集组织用于进一步分析。逆转录-聚合酶链反应（RT-PCR）也研究了蛇骨素的潜在治疗机制和涉及的信号通路，免疫印迹，一氧化氮检测，酶联免疫吸附测定，免疫组织化学，免疫荧光和流式细胞仪分析。结果Zerumbone通过抑制体外的促细胞分裂素激活蛋白激酶（MAPK）/核因子-κB信号通路，抑制了促炎细胞因子的表达，并诱导了小胶质细胞表型从经典的炎症表型转变为替代的抗炎症表型。 。经过20天的治疗后，zerumbone明显改善了转基因APP / PS1小鼠的非认知和认知行为缺陷。Zerumbone明显减少了皮质和海马中的β-淀粉样蛋白沉积并减弱了促炎性小胶质细胞活化。有趣的是 zerumbone显着增加了所有激活的小胶质细胞中抗炎小胶质细胞的比例，可能通过增强吞噬作用来减少β-淀粉样蛋白沉积。同时，骨还降低了MAPK途径关键分子的表达，例如p38和细胞外信号调节激酶。结论总的来说，蛇骨有效改善了转基因APP / PS1小鼠的行为障碍，神经炎症减弱和β-淀粉样蛋白沉积减少。Zerumbone在小胶质细胞中表现出显着的抗炎活性，并通过抑制MAPK信号通路在小胶质细胞中引起表型从促炎表型向消炎表型的转变，这可能在其神经保护作用中起重要作用。