Aging-Induced Episodic-Like Memory Impairment Could be Alleviated by Melatonin Treatment via Preserving Blood–Brain Barrier Integrity and Upregulating CRTC1

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2025-04-25 DOI:10.1111/cns.70412

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

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Abstract

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.

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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

衰老伴随着刺激识别的损伤，在老年小鼠和人类中已经发现褪黑激素水平下降。这些与年龄相关的变化与神经系统疾病的风险增加有关。在本研究中，我们的目的是研究补充褪黑激素是否可以改善老年小鼠与年龄相关的认知能力下降。方法小鼠分别给予褪黑素或生理盐水处理。新对象识别（NOR）任务用于同时评估对象和对象位置记忆，这是情景记忆的一个组成部分。采用免疫球蛋白G （IgG）渗漏试验评估血脑屏障（BBB）渗漏。免疫荧光和Western blot分析观察蛋白水平的变化。结果表明，衰老会损害NOR任务中的记忆，同时突触素（SYP）、creb调控的转录辅激活因子1 （CRTC1）和磷酸化的amp激活蛋白激酶（p-AMPK）水平在前额叶皮层（PFC）和海马中降低。此外，随着血脑屏障完整性受损，衰老导致PFC和海马的occludin降解。我们的研究结果表明，衰老会损害NOR任务中的记忆表现，并伴随着PFC和海马体中SYP、CRTC1和p-AMPK水平的降低。此外，随着血脑屏障完整性受损，衰老导致PFC和海马的occludin降解。更重要的是，在褪黑素处理的小鼠中，PDZ和LIM结构域5 （Pldim5）上调，并且在Pdlim5−/−小鼠中，NOR任务中衰老相关的记忆损伤显著减少。值得注意的是，1周的褪黑激素（10mg /kg）治疗显著改善了记忆，同时增强了血脑屏障完整性，Pdlim5下调，CRTC1和p-AMPK上调。综上所述，我们的研究结果表明，褪黑激素通过下调老年小鼠的Pdlim5、维持血脑屏障完整性、上调CRTC1和p-AMPK来改善NOR任务中与衰老相关的记忆衰退。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

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.