Wang Yanping, Zhang Xinyu, Guo Hui, Qian Shuxia, Fang Hailun, Wu Xiaoqiang, Shen Yufei, Xu Congying, Zhou Beiqun, Guo Chun, Lu Xudong, Zhang Xiaoling, Jin Xinchun
Department of Neurology, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China.
Institute of Neuroscience, The Second Affiliated Hospital of Soochow University, Suzhou, China.
CNS Neurosci Ther. 2025 Apr;31(4):e70412. doi: 10.1111/cns.70412.
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.
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.
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.
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.
衰老伴随着刺激识别能力的受损，并且在老年小鼠和人类中已显示褪黑素水平降低。这些与年龄相关的变化与神经疾病风险增加有关。在本研究中，我们的目的是调查补充褪黑素是否可以改善老年小鼠与年龄相关的认知衰退。
用褪黑素或生理盐水处理小鼠。新颖物体识别（NOR）任务用于同时评估物体和物体位置记忆，这是情景样记忆的一个组成部分。使用免疫球蛋白G（IgG）渗漏测定法评估血脑屏障（BBB）渗漏。采用免疫荧光和蛋白质印迹分析来研究蛋白质水平的变化。
我们证明衰老会损害NOR任务中的记忆，同时前额叶皮质（PFC）和海马体内的突触素（SYP）、CREB调节的转录共激活因子1（CRTC1）以及磷酸化的AMP激活蛋白激酶（p-AMPK）水平会降低。此外，除了血脑屏障完整性受损外，衰老还会导致PFC和海马体中闭合蛋白的降解。我们的研究结果表明，衰老会损害NOR任务中的记忆表现，同时伴随着PFC和海马体内SYP、CRTC1和p-AMPK水平的降低。此外，除了血脑屏障完整性受损外，衰老还会导致PFC和海马体中闭合蛋白的降解。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任务中与衰老相关的记忆障碍显著降低。值得注意的是，1周的褪黑素（10mg/kg）治疗显著改善了记忆，同时增强了血脑屏障完整性、下调了Pdlim5以及上调了CRTC1和p-AMPK。
综上所述，我们的研究结果表明，褪黑素通过下调Pdlim5、维持血脑屏障完整性以及上调老年小鼠中的CRTC1和p-AMPK来改善NOR任务中与衰老相关的记忆衰退。
