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| 去泛素化酶14抑制剂IU1对阿尔茨海默病小鼠认知功能的影响 |
| Effect of deubiquitinase 14 inhibitor IU1 on cognitive function in Alzheimer's disease mice |
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| DOI：10.12089/jca.2026.03.012 |
| 中文关键词: 去泛素化酶14 Tau蛋白 突触 认知功能障碍 |
| 英文关键词: Ubiquitin-specific protease 14 Tau protein Synapse Cognitive dysfunction |
| 基金项目:国家自然科学基金面上项目（82471281，82072130） |
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| 中文摘要: |
目的： 探究去泛素化酶14（USP14）抑制剂IU1对阿尔茨海默病（AD）小鼠认知功能的影响及相关机制。
方法： 选择健康SPF级雄性C57BL/6J小鼠36只，8～12周龄，体重22～30 g。采用随机数字表法将小鼠分为三组：对照组（C组）、AD模型组（A组）和USP14抑制剂IU1治疗组（I组），每组12只。C组为正常健康的C57BL/6J小鼠；A组采用化学造模法对C57BL/6J小鼠脑立体定位注射冈田酸诱导tau过度磷酸化，建立AD模型；I组建立AD模型，并于建立模型前1 h至建立模型后7 d给予IU1 400 μg/kg腹腔注射治疗，每天1次，共8次。于建立模型后14 d采用新物体识别实验记录探索情况和运动轨迹并计算新物体识别偏好指数，于建立模型后21 d处死小鼠，采用Western blot法检测小鼠海马组织USP14蛋白含量和tau磷酸化水平（ptau S396），采用免疫荧光实验检测小鼠海马突触蛋白Synapsin-1和PSD95表达情况，采用高尔基染色法检测小鼠海马CA1区树突棘数量。
结果： 与C组比较，A组新物体识别偏好指数明显降低，海马组织USP14和ptau S396蛋白含量明显升高，海马组织CA1区Synapsin-1和PSD95表达明显降低，共定位明显减少，树突棘数量明显减少（P＜0.05）；I组海马组织CA1区PSD95表达明显降低，共定位明显减少，树突棘数量明显减少（P＜0.05）。与A组比较，I组新物体识别偏好指数明显升高，海马组织USP14和ptau S396蛋白含量明显降低，海马组织CA1区Synapsin-1和PSD95表达明显升高，共定位明显增加，树突棘数量明显增加（P＜0.05）。
结论： IU1通过抑制USP14缓解AD小鼠认知功能障碍，其机制可能与减轻tau过度磷酸化恢复突触完整性相关。 |
| 英文摘要: |
Objective: To investigate effect and mechanism of ubiquitin-specific protease 14 (USP14) inhibitor IU1 on cognitive function in Alzheimer's disease (AD) mice.
Methods: Thirty-six healthy male SPF C57BL/6J mice, 8-12 weeks, weighting 22-30 g, were randomized into three groups: the control group (group C), the AD model group (group A), and the USP14 inhibitor IU1 treatment group (group I), 12 mice in each group. Group C were normal and healthy C57BL/6J mice, group A used Okadaic acid inducing tau hyperphosphorylation was injected stereotactically into C57BL/6J mice to establish AD model by chemical modeling, and group I were AD mice receiving intraperitoneal IU1 400 μg/kg 1 hour before the AD modeling to 7 days after the modeling, once a day for a total of 8 days. On day 14 after the modeling, novel object recognition test was applied to record the exploration situation and motion trajectory, and the novel object recognition preference index was calculated to assess the cognitive function. On day 21 after the modeling, mice were sacrificed. Western blot experiment was used to detect the protein expression of USP14 and tau phosphorylation levels (ptau S396) in hippocampal tissues. Immunofluorescence experiment was employed to detect the expression of hippocampal synaptic proteins Synapsin-1 and PSD95 in mice, and Golgi staining was used to detect the number of dendritic spines in the hippocampal CA1 region.
Results: Compared with group C, the novel object recognition preference index was significantly decreased, the hippocampal USP14 levels and ptau S369 were significantly increased,the Synapsin-1, PSD95, and their co-localization, and CA1 dendritic spine density were significantly decreased in group A (P < 0.05), the PSD95 levels and co-localization of Synapsin-1 and PSD95, and CA1 dendritic spine density were significantly decreased in group Ⅰ (P < 0.05). Compared with group A, the novel object recognition preference index was significantly increased, the USP14 and pTau S396 expression were significantly decreased, the expression of Synapsin-1, PSD95, and their co-localization, and spine density in CA1 region were significantly increased in group Ⅰ (P < 0.05).
Conclusion: IU1 ameliorates cognitive deficits in AD mice via USP14 inhibition, wherein the mechanism potentially linked to reducing tau hyperphosphorylation and restoring synaptic integrity. |
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