山茱萸醇提物调节LSD1/PSD95对Aβ25-35诱导的阿尔茨海默病小鼠神经损伤保护作用的研究
R285.5; 目的 探究山茱萸醇提物通过调节组蛋白特异性去甲基化酶1(LSD1)/突触后致密蛋白-95(PSD95)影响神经元突触和神经炎症对β淀粉样蛋白25-35(Aβ25-35)诱导的阿尔茨海默病(AD)小鼠神经损伤的保护作用.方法 将40只C57BL/6N小鼠按体质量随机分为假手术组、模型组、山茱萸醇提物低剂量组(0.1 mg/g)及山茱萸醇提物高剂量组(0.3 mg/g),每组10只.除假手术组外,其余各组双侧海马内注射Aβ25-35构建AD小鼠模型.造模前7 d开始灌胃,手术后5 d继续灌胃,共60 d.Morris水迷宫实验、Y迷宫实验及旷场实验检测小鼠学习记忆和空间探索能力;蛋...
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| Published in | 北京中医药大学学报 Vol. 47; no. 3; pp. 352 - 363 |
|---|---|
| Main Authors | , , , , , , , , |
| Format | Journal Article |
| Language | Chinese |
| Published |
河南中医药大学中医药科学院 郑州 450046%河南中医药大学中医药科学院 郑州 450046
01.03.2024
河南中医药大学第一附属医院 |
| Subjects | |
| Online Access | Get full text |
| ISSN | 1006-2157 |
| DOI | 10.3969/j.issn.1006-2157.2024.03.010 |
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| Abstract | R285.5; 目的 探究山茱萸醇提物通过调节组蛋白特异性去甲基化酶1(LSD1)/突触后致密蛋白-95(PSD95)影响神经元突触和神经炎症对β淀粉样蛋白25-35(Aβ25-35)诱导的阿尔茨海默病(AD)小鼠神经损伤的保护作用.方法 将40只C57BL/6N小鼠按体质量随机分为假手术组、模型组、山茱萸醇提物低剂量组(0.1 mg/g)及山茱萸醇提物高剂量组(0.3 mg/g),每组10只.除假手术组外,其余各组双侧海马内注射Aβ25-35构建AD小鼠模型.造模前7 d开始灌胃,手术后5 d继续灌胃,共60 d.Morris水迷宫实验、Y迷宫实验及旷场实验检测小鼠学习记忆和空间探索能力;蛋白质印迹法检测小鼠海马LSD1、PSD95、突触素(SYN)、白细胞介素-1β(IL-1β)、肿瘤坏死因子-α(TNF-α)蛋白表达及组蛋白H3第9位赖氨酸二甲基化(H3K9me2)修饰水平;染色质免疫共沉淀(CHIP)结合实时荧光PCR法检测PSD95基因启动子区H3K9me2修饰水平及PSD95 mRNA水平;组织免疫荧光法检测H3K9me2和PSD95表达的相关性及海马组织内离子钙结合衔接分子1(IBA1)的表达.结果 山茱萸醇提物能明显改善Aβ25-35诱导的阿尔茨海默病小鼠学习及记忆能力.与模型组比较,山茱萸醇提物明显缩短小鼠的逃避潜伏期,增加其自主活动次数和时间,改善其自发交替准确率,增加小鼠海马LSD1表达(均P<0.05),进而降低PSD95基因启动子区H3K9me2修饰,因此,促进PSD95 mRNA转录和蛋白表达.组织免疫荧光结果表明,山茱萸醇提物降低海马中H3K9me2修饰水平会伴随着PSD95表达的增强.山茱萸醇提物亦能抑制小胶质细胞的活化,降低促炎因子IL-1β和TNF-α的表达.结论 山茱萸醇提物可能是通过上调LSD1表达,降低PSD95基因启动子区的H3K9me2修饰水平调节基因转录,增加突触可塑性调节的关键蛋白PSD95的表达,而缓解神经炎症反应、改善AD模型小鼠学习记忆功能障碍,从而对Aβ25-35诱导的神经损伤发挥保护作用. |
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| AbstractList | R285.5; 目的 探究山茱萸醇提物通过调节组蛋白特异性去甲基化酶1(LSD1)/突触后致密蛋白-95(PSD95)影响神经元突触和神经炎症对β淀粉样蛋白25-35(Aβ25-35)诱导的阿尔茨海默病(AD)小鼠神经损伤的保护作用.方法 将40只C57BL/6N小鼠按体质量随机分为假手术组、模型组、山茱萸醇提物低剂量组(0.1 mg/g)及山茱萸醇提物高剂量组(0.3 mg/g),每组10只.除假手术组外,其余各组双侧海马内注射Aβ25-35构建AD小鼠模型.造模前7 d开始灌胃,手术后5 d继续灌胃,共60 d.Morris水迷宫实验、Y迷宫实验及旷场实验检测小鼠学习记忆和空间探索能力;蛋白质印迹法检测小鼠海马LSD1、PSD95、突触素(SYN)、白细胞介素-1β(IL-1β)、肿瘤坏死因子-α(TNF-α)蛋白表达及组蛋白H3第9位赖氨酸二甲基化(H3K9me2)修饰水平;染色质免疫共沉淀(CHIP)结合实时荧光PCR法检测PSD95基因启动子区H3K9me2修饰水平及PSD95 mRNA水平;组织免疫荧光法检测H3K9me2和PSD95表达的相关性及海马组织内离子钙结合衔接分子1(IBA1)的表达.结果 山茱萸醇提物能明显改善Aβ25-35诱导的阿尔茨海默病小鼠学习及记忆能力.与模型组比较,山茱萸醇提物明显缩短小鼠的逃避潜伏期,增加其自主活动次数和时间,改善其自发交替准确率,增加小鼠海马LSD1表达(均P<0.05),进而降低PSD95基因启动子区H3K9me2修饰,因此,促进PSD95 mRNA转录和蛋白表达.组织免疫荧光结果表明,山茱萸醇提物降低海马中H3K9me2修饰水平会伴随着PSD95表达的增强.山茱萸醇提物亦能抑制小胶质细胞的活化,降低促炎因子IL-1β和TNF-α的表达.结论 山茱萸醇提物可能是通过上调LSD1表达,降低PSD95基因启动子区的H3K9me2修饰水平调节基因转录,增加突触可塑性调节的关键蛋白PSD95的表达,而缓解神经炎症反应、改善AD模型小鼠学习记忆功能障碍,从而对Aβ25-35诱导的神经损伤发挥保护作用. |
| Abstract_FL | Objective This study investigated the protective effects of Corni Fructus ethanol extract on β-amyloid protein 25-35 (Aβ25-35)-induced Alzheimer's disease (AD) mice by regulating histone lysine-specific demethylase 1 (LSD1) / postsynaptic density protein 95 (PSD95) on synapses and neuroinflammation. Methods Specifically, according to the body weight, 40 C57BL/6N mice were randomized into four groups: the sham operation group, the model group, the low-dose (0.1mg/g) and the high-dose (0.3 mg/g) Corni Fructus ethanol extract groups. Aβ25-35 was injected into the hippocampus of mice in three groups except for the sham operation group to established AD model. All mice were orally administered with either Corni Fructus ethanol extract or vehicle by gavage for 7 days before molding and continued 5 days after surgery for a total of 60 days. Morris water maze, Y maze and open field tests were performed to evaluate the recognition memory and space exploration ability of mice. The expression of LSD1, PSD95, synaptophysin (SYN), interleukin-1β (IL-1β), tumor necrosis factor-α(TNF-α) and H3K9me2 level were measured by Western blotting. Chromatin immunoprecipitation (CHIP) combined with qPCR was used to detect H3K9me2 modification of PSD95 promoter region and mRNA levels of PSD95. The correlation between the expression of H3K9me2 and PSD95 and the expression of IBA1 in the hippocampus were detected by immunofluorescence assay.Results The result showed that Corni Fructus ethanol extract significantly reversed Aβ25-35-induced learning and memory impairment in AD mice. Compared with the model group, Corni Fructus ethanol extract demonstrated shorter escape latency, increased number and time of autonomous activities and the rate of autonomous alternation. Moreover, it increased the expression of LSD1 in hippocampus of AD mice(P<0.05), and reduced H3K9me2 modification level in the promoter region of PSD95 gene, and then promoted the mRNA transcription and protein expression of PSD95. Immunofluorescence staining indicated the reduction of H3K9me2 modification level in hippocampus was accompanied by the enhancement of PSD95 expression. Corni Fructus ethanol extract could also inhibit the activation of microglia and reduce the expression of proinflammatory factors IL-1β and TNF-α.Conclusion Corni Fructus ethanol extract may regulate PSD95 gene transcription by up-regulating the expression of LSD1 and reducing the H3K9me2 modification level in its promoter region, thereby increasing the expression of PSD95, a key protein in synaptic plasticity regulation, which alleviate neuroinflammatory response, improve learning and memory dysfunction in AD model mice, and thus play a protective role in Aβ25-35-induced nerve damage. |
| Author | 李立新 张紫娟 李中华 曾华辉 杨计歌 宋军营 马金莲 张振强 苏运芳 |
| AuthorAffiliation | 河南中医药大学中医药科学院 郑州 450046%河南中医药大学中医药科学院 郑州 450046;河南中医药大学第一附属医院 |
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| Author_FL | LI Zhonghua SU Yunfang ZHANG Zijuan ZHANG Zhenqiang LI Lixin SONG Junying ZENG Huahui YANG Jige MA Jinlian |
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| DocumentTitle_FL | Neuroprotective effect of ethanol extract of Corni Fructus on Aβ25-35- induced Alzheimer's disease mice by regulating LSD1/PSD95 |
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| Keywords | 组蛋白修饰 神经损伤 山茱萸 Corni Fructus histone modification injury of nerve lysine-specific demethylase 1 阿尔茨海默病 小鼠 Alzheimer's disease mice 组蛋白特异性去甲基化酶1 |
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| Publisher | 河南中医药大学中医药科学院 郑州 450046%河南中医药大学中医药科学院 郑州 450046 河南中医药大学第一附属医院 |
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| Title | 山茱萸醇提物调节LSD1/PSD95对Aβ25-35诱导的阿尔茨海默病小鼠神经损伤保护作用的研究 |
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