Department of Physiology, Faculty of Biology, University of Murcia, Murcia, Spain.
Chronobiol Int. 2012 Aug;29(7):822-34. doi: 10.3109/07420528.2012.699119.
Alzheimer disease (AD) is a neurodegenerative disorder that primarily causes β-amyloid accumulation in the brain, resulting in cognitive and behavioral deficits. AD patients, however, also suffer from severe circadian rhythm disruptions, and the underlying causes are still not fully known. Patients with AD show reduced systemic melatonin levels. This may contribute to their symptoms, since melatonin is an effective chronobiotic and antioxidant with neuroprotective properties. Here, the authors critically assessed the effects of long-term melatonin treatment on circadian system function, hippocampal oxidative stress, and spatial memory performance in the APPswe/PS1 double transgenic (Tg) mouse model of AD. To test if melatonin MT1/MT2 receptor activation, alone, was involved, the authors chronically treated some mice with the selective MT1/MT2 receptor agonist ramelteon. The results indicate that many of the circadian and behavioral parameters measured, including oxidative stress markers, were not significantly affected in these AD mice. During the day, though, Tg controls (Tg-CON) showed significantly higher mean activity and body temperature (BT) than wild-type (WT) mice. Overall, BT rhythm amplitude was significantly lower in Tg than in WT mice. Although melatonin treatment had no effect, ramelteon significantly reduced the amplitude of the BT rhythm in Tg mice. Towards the end of the experiment, Tg mice treated with ramelteon (Tg-RAM) showed significantly higher circadian rhythm fragmentation than Tg-CON and reduced circadian BT rhythm strength. The free-running period (τ) for the BT and locomotor activity (LA) rhythms of Tg-CON was <24 h. Whereas melatonin maintained τ at 24 h for BT and LA in both genotypes, ramelteon treatment had no effect. In the behavioral tests, the number of approaches and time spent exploring novel objects were significantly higher in Tg-CON than WT controls. Brain tissue analysis revealed significant reduction in hippocampal protein oxidation in Tg-MEL and Tg-RAM compared with Tg-CON animals. These results suggest that not all aspects of the circadian system are affected in the APPswe/PS1 mice. Therefore, care should be taken when extending the results obtained in Tg mice to develop new therapies in humans. This study also revealed the complexity in the therapeutic actions of melatonin and ramelteon in this mouse model of AD.
阿尔茨海默病（AD）是一种神经退行性疾病，主要导致大脑中β-淀粉样蛋白的积累，从而导致认知和行为缺陷。然而，AD 患者也患有严重的昼夜节律紊乱，其根本原因仍不完全清楚。AD 患者表现出系统褪黑素水平降低。这可能导致他们的症状，因为褪黑素是一种有效的生物钟调节剂和具有神经保护作用的抗氧化剂。在这里，作者批判性地评估了长期褪黑素治疗对 APPswe/PS1 双转基因（Tg）AD 小鼠模型昼夜节律系统功能、海马氧化应激和空间记忆表现的影响。为了测试褪黑素 MT1/MT2 受体激活是否单独参与，作者用选择性 MT1/MT2 受体激动剂雷美替胺长期治疗一些小鼠。结果表明，在这些 AD 小鼠中，测量的许多昼夜节律和行为参数，包括氧化应激标志物，没有显著影响。然而，在白天，Tg 对照（Tg-CON）显示出比野生型（WT）小鼠显著更高的平均活动和体温（BT）。总体而言，Tg 小鼠的 BT 节律幅度明显低于 WT 小鼠。尽管褪黑素治疗没有效果，但雷美替胺显著降低了 Tg 小鼠 BT 节律的幅度。在实验的后期，用雷美替胺治疗的 Tg 小鼠（Tg-RAM）显示出比 Tg-CON 更高的昼夜节律碎片化，并且 BT 节律强度降低。Tg-CON 的 BT 和运动活动（LA）节律的自由运行期（τ）<24 小时。而褪黑素使 BT 和 LA 在两种基因型中的 τ 保持在 24 小时，雷美替胺治疗没有效果。在行为测试中，Tg-CON 接近和探索新物体的时间明显高于 WT 对照。脑组织分析显示，与 Tg-CON 动物相比，Tg-MEL 和 Tg-RAM 中小鼠海马蛋白氧化显著减少。这些结果表明，APPswe/PS1 小鼠的昼夜节律系统并非所有方面都受到影响。因此，在将 Tg 小鼠中获得的结果扩展到开发新的人类治疗方法时，应谨慎行事。这项研究还揭示了褪黑素和雷美替胺在 AD 小鼠模型中的治疗作用的复杂性。
