{"title":"蝎毒耐热合成肽通过小胶质反转录复合物改善APP/PS1小鼠认知功能障碍。","authors":"Yue Zhang, Yu-Xia Wu, Xiao-Gang Zhang, Song-Yu Guo, Jia He, Na-Na Hu, Yue-Lin Huang, Yue Kong, Qi-Fa Li, Ao-Ran Sui, Bao-Hang Zhu, Hua Piao, Jie Zhao, Shao Li","doi":"10.1111/bph.70124","DOIUrl":null,"url":null,"abstract":"<div>\n \n <section>\n \n <h3> Background and Purpose</h3>\n \n <p>The abnormal accumulation of amyloid-β (Aβ) in the brain is a characteristic pathological change observed in patients with Alzheimer's disease (AD). Microglial phagocytosis, dependent on recycling through the retromer complex and cell membrane-bound receptors, plays a vital role in clearing Aβ from the brain. Previous studies have demonstrated the neurotrophic and neuroprotective effects of Scorpion Venom Heat-Resistant Synthetic Peptide (SVHRSP); however, its impacts on cognitive function remain unclear. The present study aims to investigate the impact of SVHRSP on cognitive function in APP/PS1 transgenic mice and underlying mechanisms associated with microglial retromer complex.</p>\n </section>\n \n <section>\n \n <h3> Experimental Approach</h3>\n \n <p>SVHRSP and 3-methyladenine (3-MA) were intraperitoneally injected at 7.5 months to investigate their effects on cognitive dysfunction in APP/PS1 mice. Following behavioural testing, brain samples were harvested 24 h later for electrophysiological recordings, analysis of protein and gene expression, and histological assessment. The role of microglial retromer complex was examined using primary microglia cultures.</p>\n </section>\n \n <section>\n \n <h3> Key Results</h3>\n \n <p>SVHRSP treatment effectively improved AD-related pathological features, including cognitive impairment, neuronal loss, impaired synaptic plasticity, neuroinflammation, and Aβ deposition in APP/PS1 mice. Both in vivo and in vitro studies revealed that SVHRSP treatment increased expression of retromer complex protein VPS35. 3-MA, a specific class III phosphoinositide 3-kinase (PI3K) inhibitor that prevents autophagosome formation, reduced retromer complex protein expression and hindered the cognitive function improvements of SVHRSP.</p>\n </section>\n \n <section>\n \n <h3> Conclusion and Implications</h3>\n \n <p>Our findings suggest that SVHRSP may enhance microglial phagocytosis by modulating retromer complex activity, thereby alleviating Aβ accumulation and improving cognitive dysfunction in AD.</p>\n </section>\n </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 21","pages":"5391-5408"},"PeriodicalIF":7.7000,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Scorpion venom heat-resistant synthetic peptide improves cognitive dysfunction of APP/PS1 mice through microglial retromer complex\",\"authors\":\"Yue Zhang, Yu-Xia Wu, Xiao-Gang Zhang, Song-Yu Guo, Jia He, Na-Na Hu, Yue-Lin Huang, Yue Kong, Qi-Fa Li, Ao-Ran Sui, Bao-Hang Zhu, Hua Piao, Jie Zhao, Shao Li\",\"doi\":\"10.1111/bph.70124\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n <section>\\n \\n <h3> Background and Purpose</h3>\\n \\n <p>The abnormal accumulation of amyloid-β (Aβ) in the brain is a characteristic pathological change observed in patients with Alzheimer's disease (AD). Microglial phagocytosis, dependent on recycling through the retromer complex and cell membrane-bound receptors, plays a vital role in clearing Aβ from the brain. Previous studies have demonstrated the neurotrophic and neuroprotective effects of Scorpion Venom Heat-Resistant Synthetic Peptide (SVHRSP); however, its impacts on cognitive function remain unclear. The present study aims to investigate the impact of SVHRSP on cognitive function in APP/PS1 transgenic mice and underlying mechanisms associated with microglial retromer complex.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Experimental Approach</h3>\\n \\n <p>SVHRSP and 3-methyladenine (3-MA) were intraperitoneally injected at 7.5 months to investigate their effects on cognitive dysfunction in APP/PS1 mice. Following behavioural testing, brain samples were harvested 24 h later for electrophysiological recordings, analysis of protein and gene expression, and histological assessment. 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引用次数: 0
摘要
背景与目的：淀粉样蛋白-β (a β)在大脑中的异常积累是阿尔茨海默病（AD）患者的特征性病理改变。小胶质细胞吞噬作用依赖于通过反转录复合物和细胞膜结合受体的循环，在清除大脑中的a β中起着至关重要的作用。研究表明，蝎毒耐热合成肽（SVHRSP）具有神经营养和神经保护作用；然而，它对认知功能的影响尚不清楚。本研究旨在探讨SVHRSP对APP/PS1转基因小鼠认知功能的影响及其与小胶质逆转录复合物相关的潜在机制。实验方法：7.5月龄时腹腔注射SVHRSP和3-甲基腺嘌呤（3-MA），观察其对APP/PS1小鼠认知功能障碍的影响。行为测试后，24小时后采集脑样本进行电生理记录、蛋白质和基因表达分析以及组织学评估。用原代小胶质细胞培养检测小胶质细胞后转录复合物的作用。关键结果：SVHRSP治疗可有效改善APP/PS1小鼠ad相关病理特征，包括认知功能障碍、神经元丧失、突触可塑性受损、神经炎症和Aβ沉积。体内和体外研究均表明，SVHRSP处理增加了逆转录复合体蛋白VPS35的表达。3-MA，一种特异性III类磷酸肌苷3激酶（PI3K）抑制剂，可阻止自噬体形成，降低逆转录复合物蛋白表达，阻碍SVHRSP认知功能的改善。结论和意义：SVHRSP可能通过调节逆转录复合物活性来增强小胶质细胞吞噬，从而减轻Aβ积累，改善AD患者的认知功能障碍。
Scorpion venom heat-resistant synthetic peptide improves cognitive dysfunction of APP/PS1 mice through microglial retromer complex
Background and Purpose
The abnormal accumulation of amyloid-β (Aβ) in the brain is a characteristic pathological change observed in patients with Alzheimer's disease (AD). Microglial phagocytosis, dependent on recycling through the retromer complex and cell membrane-bound receptors, plays a vital role in clearing Aβ from the brain. Previous studies have demonstrated the neurotrophic and neuroprotective effects of Scorpion Venom Heat-Resistant Synthetic Peptide (SVHRSP); however, its impacts on cognitive function remain unclear. The present study aims to investigate the impact of SVHRSP on cognitive function in APP/PS1 transgenic mice and underlying mechanisms associated with microglial retromer complex.
Experimental Approach
SVHRSP and 3-methyladenine (3-MA) were intraperitoneally injected at 7.5 months to investigate their effects on cognitive dysfunction in APP/PS1 mice. Following behavioural testing, brain samples were harvested 24 h later for electrophysiological recordings, analysis of protein and gene expression, and histological assessment. The role of microglial retromer complex was examined using primary microglia cultures.
Key Results
SVHRSP treatment effectively improved AD-related pathological features, including cognitive impairment, neuronal loss, impaired synaptic plasticity, neuroinflammation, and Aβ deposition in APP/PS1 mice. Both in vivo and in vitro studies revealed that SVHRSP treatment increased expression of retromer complex protein VPS35. 3-MA, a specific class III phosphoinositide 3-kinase (PI3K) inhibitor that prevents autophagosome formation, reduced retromer complex protein expression and hindered the cognitive function improvements of SVHRSP.
Conclusion and Implications
Our findings suggest that SVHRSP may enhance microglial phagocytosis by modulating retromer complex activity, thereby alleviating Aβ accumulation and improving cognitive dysfunction in AD.
期刊介绍：
The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries.
Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues.
In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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