Background:Dysfunction of synaptic plasticity leads to memory impairment in Alzheimer’s disease (AD). Muscone (Mus) has shown neuroprotective effects in cerebral ischemic models. However, little is known of Mus effects on AD. Objective:To investigate the effects of Mus on memory functions and synaptic plasticity in 6-month-old APP/PS1 double-transgenic mice and explore the potential mechanisms. Methods:Mus was intraperitoneally injected into APP/PS1 or wild-type mice, and cognitive function was assessed by Novel object recognition and Morris water maze tests. The levels of amyloid-β (Aβ) were evaluated by immunofluorescence staining and ELISA. Synaptic morphology and plasticity were evaluated by Golgi staining and long-term potentiation. Cell viability was examined by Cell Counting Kit-8 assay. The protein levels of histone deacetylase 2 (HDAC2) were accessed by western blotting and Immunofluorescence staining. The protein levels of microtubule associated protein 2 and synaptophysin were analyzed by immunofluorescence staining. The ubiquitination of HDAC2 was examined by co-immunoprecipitation. The interaction of Mus with HDAC2 was predicted by molecular docking analysis. Results:Mus treatment attenuated memory dysfunction, reduced Aβ level, and enhanced synaptic plasticity in APP/PS1 mice. In addition, Mus treatment decreased the level of HDAC2 in the hippocampus of APP/PS1 mice and Aβ1–42-induced primary neurons, which might be associated with increased HDAC2 ubiquitination induced by HDAC2 and Mus interaction. Conclusion:Mus protected against synaptic plasticity and memory impairment in APP/PS1 mice, and enhanced HDAC2 degradation via ubiquitination, indicating that Mus was a potential drug for AD treatment.

中文翻译：

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Muscone改善APP / PS1小鼠的突触功能障碍和认知缺陷。

背景：突触可塑性的功能障碍导致阿尔茨海默氏病（AD）的记忆障碍。Muscone（Mus）在脑缺血模型中显示出神经保护作用。但是，关于Mus对AD的影响知之甚少。目的：研究Mus对6个月大APP / PS1双转基因小鼠记忆功能和突触可塑性的影响，并探讨其潜在机制。方法：将小鼠腹膜内注射至APP / PS1或野生型小鼠中，并通过新型物体识别和莫里斯水迷宫测试评估其认知功能。通过免疫荧光染色和ELISA评估淀粉样β（Aβ）的水平。通过高尔基染色和长期增强来评估突触的形态和可塑性。细胞活力通过Cell Counting Kit-8测定法检查。蛋白质组蛋白脱乙酰基酶2（HDAC2）的蛋白质水平通过蛋白质印迹和免疫荧光染色获得。通过免疫荧光染色分析微管相关蛋白2和突触素的蛋白水平。通过共免疫沉淀检测HDAC2的泛素化。通过分子对接分析预测了Mus与HDAC2的相互作用。结果：Mus治疗可减轻APP / PS1小鼠的记忆功能障碍，降低Aβ水平并增强突触可塑性。此外，Mus治疗降低了APP / PS1小鼠和Aβ1-42诱导的原代神经元海马中HDAC2的水平，这可能与HDAC2和Mus相互作用引起的HDAC2泛素化增加有关。结论：Mus可以保护APP / PS1小鼠免受突触可塑性和记忆力的损害，