GLP-1受体激动剂semaglutide改善rTg4510s小鼠模型的运动缺陷和tau病理

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology Pub Date : 2025-08-27 DOI:10.1016/j.neuropharm.2025.110659

Meng-Wei Zhang , Wan-Yi Zhou , Xin-Yi Li , Zhi-Heng Xu , Hua-Mei Lin , Yi-Lin Tang , Jue Zhao , Chen Chen , Feng-Tao Liu , Yi-Min Sun , Chuan-Tao Zuo , Jian-Jun Wu , Jian Wang , Wen-Bo Yu

{"title":"GLP-1受体激动剂semaglutide改善rTg4510s小鼠模型的运动缺陷和tau病理","authors":"Meng-Wei Zhang , Wan-Yi Zhou , Xin-Yi Li , Zhi-Heng Xu , Hua-Mei Lin , Yi-Lin Tang , Jue Zhao , Chen Chen , Feng-Tao Liu , Yi-Min Sun , Chuan-Tao Zuo , Jian-Jun Wu , Jian Wang , Wen-Bo Yu","doi":"10.1016/j.neuropharm.2025.110659","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Tauopathies, including Alzheimer's disease, are characterized by progressive neurodegeneration manifesting as motor and cognitive impairments. This study evaluated the therapeutic potential of semaglutide, a clinically approved glucagon-like peptide-1 receptor agonist, in the rTg4510 mouse model of tauopathy.</div></div><div><h3>Methods</h3><div>Starting at three months of age, rTg4510 mice and wild-type littermates received semaglutide (0.10 mg kg<sup>−1</sup>, intraperitoneal) or vehicle (PBS) every other day for 16 weeks. Motor coordination, anxiety-like behavior, spatial working memory, and associative fear memory were assessed using behavioral paradigms. Tau accumulation was monitored via 18F-PM-PBB3 micro-PET/CT imaging. Immunohistochemistry and immunoblot analyses quantified tau pathology, neuronal integrity, and glial activation.</div></div><div><h3>Results</h3><div>Semaglutide significantly improved motor coordination in rTg4510 mice on the pole test, though not rotarod endurance. While spontaneous locomotion, anxiety-like behaviors, and Y-maze spatial working memory remained unchanged, semaglutide significantly enhanced cue-dependent freezing in fear conditioning, indicating improved associative memory. <sup>18</sup>F-PM-PBB3 PET imaging revealed a pronounced reduction in cortical and hippocampal tracer uptake, indicative of reduced tau burden. Immunohistochemistry and Western blotting confirmed significantly decreased cortical phosphorylated tau (AT8) levels. Semaglutide preserved cortical neuronal integrity; however, no hippocampal changes were detected, likely due to minimal baseline neuron loss at this age. Astrocytic (GFAP) and microglial (Iba1) activation remained unaffected.</div></div><div><h3>Conclusion</h3><div>Semaglutide ameliorated domain-specific motor impairments, enhanced associative fear memory, and attenuated cortical tau pathology in rTg4510 mice. These findings highlight therapeutic promise of semaglutide as a disease-modifying agent for tauopathies, justifying further dose-response, mechanistic, and translational studies.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"280 ","pages":"Article 110659"},"PeriodicalIF":4.6000,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"GLP-1 receptor agonist semaglutide ameliorates motor deficits and tau pathology in the rTg4510s mouse model\",\"authors\":\"Meng-Wei Zhang , Wan-Yi Zhou , Xin-Yi Li , Zhi-Heng Xu , Hua-Mei Lin , Yi-Lin Tang , Jue Zhao , Chen Chen , Feng-Tao Liu , Yi-Min Sun , Chuan-Tao Zuo , Jian-Jun Wu , Jian Wang , Wen-Bo Yu\",\"doi\":\"10.1016/j.neuropharm.2025.110659\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><div>Tauopathies, including Alzheimer's disease, are characterized by progressive neurodegeneration manifesting as motor and cognitive impairments. This study evaluated the therapeutic potential of semaglutide, a clinically approved glucagon-like peptide-1 receptor agonist, in the rTg4510 mouse model of tauopathy.</div></div><div><h3>Methods</h3><div>Starting at three months of age, rTg4510 mice and wild-type littermates received semaglutide (0.10 mg kg<sup>−1</sup>, intraperitoneal) or vehicle (PBS) every other day for 16 weeks. Motor coordination, anxiety-like behavior, spatial working memory, and associative fear memory were assessed using behavioral paradigms. Tau accumulation was monitored via 18F-PM-PBB3 micro-PET/CT imaging. Immunohistochemistry and immunoblot analyses quantified tau pathology, neuronal integrity, and glial activation.</div></div><div><h3>Results</h3><div>Semaglutide significantly improved motor coordination in rTg4510 mice on the pole test, though not rotarod endurance. While spontaneous locomotion, anxiety-like behaviors, and Y-maze spatial working memory remained unchanged, semaglutide significantly enhanced cue-dependent freezing in fear conditioning, indicating improved associative memory. <sup>18</sup>F-PM-PBB3 PET imaging revealed a pronounced reduction in cortical and hippocampal tracer uptake, indicative of reduced tau burden. Immunohistochemistry and Western blotting confirmed significantly decreased cortical phosphorylated tau (AT8) levels. Semaglutide preserved cortical neuronal integrity; however, no hippocampal changes were detected, likely due to minimal baseline neuron loss at this age. Astrocytic (GFAP) and microglial (Iba1) activation remained unaffected.</div></div><div><h3>Conclusion</h3><div>Semaglutide ameliorated domain-specific motor impairments, enhanced associative fear memory, and attenuated cortical tau pathology in rTg4510 mice. These findings highlight therapeutic promise of semaglutide as a disease-modifying agent for tauopathies, justifying further dose-response, mechanistic, and translational studies.</div></div>\",\"PeriodicalId\":19139,\"journal\":{\"name\":\"Neuropharmacology\",\"volume\":\"280 \",\"pages\":\"Article 110659\"},\"PeriodicalIF\":4.6000,\"publicationDate\":\"2025-08-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neuropharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0028390825003673\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neuropharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0028390825003673","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}

引用次数: 0

摘要

背景：包括阿尔茨海默病在内的tau病以进行性神经变性为特征，表现为运动和认知障碍。本研究评估了semaglutide（一种临床批准的胰高血糖素样肽-1受体激动剂）在rTg4510小鼠牛头病模型中的治疗潜力。方法从3月龄开始，rTg4510小鼠和野生型窝仔每隔一天接受西马鲁肽（0.10 mg kg−1，腹腔注射）或对照物（PBS），持续16周。采用行为范式评估运动协调、类焦虑行为、空间工作记忆和联想恐惧记忆。通过18F-PM-PBB3微pet /CT成像监测Tau积聚。免疫组织化学和免疫印迹分析定量tau病理，神经元完整性和胶质细胞活化。结果semaglutide可显著改善rTg4510小鼠的运动协调性，但对旋转耐力无显著改善作用。在自发运动、类焦虑行为和y型迷宫空间工作记忆保持不变的情况下，西马鲁肽显著增强了恐惧条件反射中的线索依赖冻结，表明联想记忆得到改善。18F-PM-PBB3 PET成像显示皮质和海马示踪剂摄取明显减少，表明tau负担减少。免疫组织化学和Western blotting证实皮质磷酸化tau （AT8）水平显著降低。Semaglutide保留皮质神经元的完整性；然而，没有检测到海马的变化，可能是由于这个年龄的基线神经元损失最小。星形胶质细胞（GFAP）和小胶质细胞（Iba1）的激活未受影响。结论semaglutide改善了rTg4510小鼠的区域特异性运动损伤，增强了联想恐惧记忆，减轻了皮质tau病理。这些发现突出了西马鲁肽作为一种疾病调节剂治疗牛头病变的前景，证明了进一步的剂量反应、机制和转化研究是合理的。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

查看原文本刊更多论文

GLP-1 receptor agonist semaglutide ameliorates motor deficits and tau pathology in the rTg4510s mouse model

Background

Tauopathies, including Alzheimer's disease, are characterized by progressive neurodegeneration manifesting as motor and cognitive impairments. This study evaluated the therapeutic potential of semaglutide, a clinically approved glucagon-like peptide-1 receptor agonist, in the rTg4510 mouse model of tauopathy.

Methods

Starting at three months of age, rTg4510 mice and wild-type littermates received semaglutide (0.10 mg kg⁻¹, intraperitoneal) or vehicle (PBS) every other day for 16 weeks. Motor coordination, anxiety-like behavior, spatial working memory, and associative fear memory were assessed using behavioral paradigms. Tau accumulation was monitored via 18F-PM-PBB3 micro-PET/CT imaging. Immunohistochemistry and immunoblot analyses quantified tau pathology, neuronal integrity, and glial activation.

Results

Semaglutide significantly improved motor coordination in rTg4510 mice on the pole test, though not rotarod endurance. While spontaneous locomotion, anxiety-like behaviors, and Y-maze spatial working memory remained unchanged, semaglutide significantly enhanced cue-dependent freezing in fear conditioning, indicating improved associative memory. ¹⁸F-PM-PBB3 PET imaging revealed a pronounced reduction in cortical and hippocampal tracer uptake, indicative of reduced tau burden. Immunohistochemistry and Western blotting confirmed significantly decreased cortical phosphorylated tau (AT8) levels. Semaglutide preserved cortical neuronal integrity; however, no hippocampal changes were detected, likely due to minimal baseline neuron loss at this age. Astrocytic (GFAP) and microglial (Iba1) activation remained unaffected.

Conclusion

Semaglutide ameliorated domain-specific motor impairments, enhanced associative fear memory, and attenuated cortical tau pathology in rTg4510 mice. These findings highlight therapeutic promise of semaglutide as a disease-modifying agent for tauopathies, justifying further dose-response, mechanistic, and translational studies.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊

Neuropharmacology 医学-神经科学

CiteScore

10.00

自引率

4.30%

发文量

288

审稿时长

45 days

期刊介绍： Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).