{"title":"褪黑素治疗可通过维持血脑屏障完整性和上调CRTC1来缓解衰老引起的情景样记忆障碍","authors":"Yanping Wang, Xinyu Zhang, Hui Guo, Shuxia Qian, Hailun Fang, Xiaoqiang Wu, Yufei Shen, Congying Xu, Beiqun Zhou, Chun Guo, Xudong Lu, Xiaoling Zhang, Xinchun Jin","doi":"10.1111/cns.70412","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>Aging is accompanied by impairments in stimulus recognition, and decreased melatonin levels have been shown in aged mice and humans. These age-related changes are associated with an increased risk of neurological diseases. In the present study, our aim is to investigate whether melatonin supplementation could ameliorate age-related cognitive decline in aged mice.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>Mice were treated with melatonin or saline. The novel object recognition (NOR) task was used to provide a simultaneous assessment of object and object location memory, which is a component of episodic-like memory. Blood–brain barrier (BBB) leakage was assessed using an Immunoglobulin G (IgG) leakage assay. Immunofluorescence and Western blot analyses were employed to investigate changes in protein levels.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>We demonstrate that aging impairs memory in the NOR task, with concomitant decreases in the levels of synaptophysin (SYP), CREB-regulated transcription coactivator 1 (CRTC1), and phosphorylated AMP-activated protein kinase (p-AMPK) levels within the prefrontal cortex (PFC) and hippocampus. Moreover, alongside compromised BBB integrity, aging results in the degradation of occludin in both the PFC and hippocampus. Our findings demonstrate that aging impairs memory performance in the NOR task, accompanied by reductions in SYP, CRTC1, and p-AMPK levels within the PFC and hippocampus. Furthermore, alongside compromised BBB integrity, aging results in the degradation of occludin in both the PFC and hippocampus. More importantly, PDZ and LIM domain 5 (Pldim5) was upregulated in melatonin-treated mice, and aging-related memory impairment in the NOR task was significantly reduced in Pdlim5<sup>−/−</sup> mice. Notably, 1 week of melatonin (10 mg/kg) treatment significantly improved memory, along with enhanced BBB integrity, Pdlim5 downregulation, and CRTC1 and p-AMPK upregulation.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>Taken together, our findings suggest that melatonin ameliorates aging-related memory decline in the NOR task by downregulating Pdlim5, maintaining BBB integrity, and upregulating CRTC1 and p-AMPK in aged mice.</p>\n </section>\n </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 4","pages":""},"PeriodicalIF":4.8000,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70412","citationCount":"0","resultStr":"{\"title\":\"Aging-Induced Episodic-Like Memory Impairment Could be Alleviated by Melatonin Treatment via Preserving Blood–Brain Barrier Integrity and Upregulating CRTC1\",\"authors\":\"Yanping Wang, Xinyu Zhang, Hui Guo, Shuxia Qian, Hailun Fang, Xiaoqiang Wu, Yufei Shen, Congying Xu, Beiqun Zhou, Chun Guo, Xudong Lu, Xiaoling Zhang, Xinchun Jin\",\"doi\":\"10.1111/cns.70412\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background</h3>\\n \\n <p>Aging is accompanied by impairments in stimulus recognition, and decreased melatonin levels have been shown in aged mice and humans. These age-related changes are associated with an increased risk of neurological diseases. In the present study, our aim is to investigate whether melatonin supplementation could ameliorate age-related cognitive decline in aged mice.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>Mice were treated with melatonin or saline. The novel object recognition (NOR) task was used to provide a simultaneous assessment of object and object location memory, which is a component of episodic-like memory. Blood–brain barrier (BBB) leakage was assessed using an Immunoglobulin G (IgG) leakage assay. Immunofluorescence and Western blot analyses were employed to investigate changes in protein levels.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>We demonstrate that aging impairs memory in the NOR task, with concomitant decreases in the levels of synaptophysin (SYP), CREB-regulated transcription coactivator 1 (CRTC1), and phosphorylated AMP-activated protein kinase (p-AMPK) levels within the prefrontal cortex (PFC) and hippocampus. Moreover, alongside compromised BBB integrity, aging results in the degradation of occludin in both the PFC and hippocampus. Our findings demonstrate that aging impairs memory performance in the NOR task, accompanied by reductions in SYP, CRTC1, and p-AMPK levels within the PFC and hippocampus. Furthermore, alongside compromised BBB integrity, aging results in the degradation of occludin in both the PFC and hippocampus. More importantly, PDZ and LIM domain 5 (Pldim5) was upregulated in melatonin-treated mice, and aging-related memory impairment in the NOR task was significantly reduced in Pdlim5<sup>−/−</sup> mice. Notably, 1 week of melatonin (10 mg/kg) treatment significantly improved memory, along with enhanced BBB integrity, Pdlim5 downregulation, and CRTC1 and p-AMPK upregulation.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusions</h3>\\n \\n <p>Taken together, our findings suggest that melatonin ameliorates aging-related memory decline in the NOR task by downregulating Pdlim5, maintaining BBB integrity, and upregulating CRTC1 and p-AMPK in aged mice.</p>\\n </section>\\n </div>\",\"PeriodicalId\":154,\"journal\":{\"name\":\"CNS Neuroscience & Therapeutics\",\"volume\":\"31 4\",\"pages\":\"\"},\"PeriodicalIF\":4.8000,\"publicationDate\":\"2025-04-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cns.70412\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"CNS Neuroscience & Therapeutics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/cns.70412\",\"RegionNum\":1,\"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":"CNS Neuroscience & Therapeutics","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/cns.70412","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Aging-Induced Episodic-Like Memory Impairment Could be Alleviated by Melatonin Treatment via Preserving Blood–Brain Barrier Integrity and Upregulating CRTC1
Background
Aging is accompanied by impairments in stimulus recognition, and decreased melatonin levels have been shown in aged mice and humans. These age-related changes are associated with an increased risk of neurological diseases. In the present study, our aim is to investigate whether melatonin supplementation could ameliorate age-related cognitive decline in aged mice.
Methods
Mice were treated with melatonin or saline. The novel object recognition (NOR) task was used to provide a simultaneous assessment of object and object location memory, which is a component of episodic-like memory. Blood–brain barrier (BBB) leakage was assessed using an Immunoglobulin G (IgG) leakage assay. Immunofluorescence and Western blot analyses were employed to investigate changes in protein levels.
Results
We demonstrate that aging impairs memory in the NOR task, with concomitant decreases in the levels of synaptophysin (SYP), CREB-regulated transcription coactivator 1 (CRTC1), and phosphorylated AMP-activated protein kinase (p-AMPK) levels within the prefrontal cortex (PFC) and hippocampus. Moreover, alongside compromised BBB integrity, aging results in the degradation of occludin in both the PFC and hippocampus. Our findings demonstrate that aging impairs memory performance in the NOR task, accompanied by reductions in SYP, CRTC1, and p-AMPK levels within the PFC and hippocampus. Furthermore, alongside compromised BBB integrity, aging results in the degradation of occludin in both the PFC and hippocampus. More importantly, PDZ and LIM domain 5 (Pldim5) was upregulated in melatonin-treated mice, and aging-related memory impairment in the NOR task was significantly reduced in Pdlim5−/− mice. Notably, 1 week of melatonin (10 mg/kg) treatment significantly improved memory, along with enhanced BBB integrity, Pdlim5 downregulation, and CRTC1 and p-AMPK upregulation.
Conclusions
Taken together, our findings suggest that melatonin ameliorates aging-related memory decline in the NOR task by downregulating Pdlim5, maintaining BBB integrity, and upregulating CRTC1 and p-AMPK in aged mice.
期刊介绍：
CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
