Abnormal Clock Gene Expression and Locomotor Activity Rhythms in Two Month-Old Female APPSwe/PS1dE9 Mice
Abnormal Clock Gene Expression and Locomotor Activity Rhythms in Two Month-Old Female APPSwe/PS1dE9 Mice
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DOI：
10.2174/1567205014666170317113159
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发表时间：
2017-01-01
影响因子：
2.1
通讯作者：
Moran, Paula M.
中科院分区：
文献类型：
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作者：
Oyegbami, Olaide;Collins, Hilary M.;Moran, Paula M.
背景：除了认知能力下降外，阿尔茨海默病（AD）还以躁动、活动和睡眠中断为特征。这些症状通常发生在傍晚或夜间，被称为“日落”。它们对护理人员来说尤其困难，而且没有特定的药物治疗。越来越多的证据表明，这些症状反映了昼夜节律产生和传递的病理。目的：研究与AD相关的转基因小鼠模型（APPswe/PS1dE9）在其家笼中运动活动是否出现昼夜节律改变，以及从这些小鼠分离的海马和脑髓-脑桥区域参与昼夜节律调节的时钟基因表达是否异常。结果：2月龄雌性小鼠的APPswe/ PS1dE9基因改变了运动活动的昼夜节律水平和模式。在野生型对照小鼠的髓质/脑桥中，生物钟基因Per1、Per2、Cry1和Cry2的表达在夜间比白天增加。对Cry1和Cry2基因在APPswe/PS1dE9中的表达的影响减弱。结论：本研究表明，运动活动的昼夜节律调节改变在雌性APPswe/PS1dE9小鼠中是异常的，这种改变在广泛存在的AD模型中具有生物分子相似性。这些影响在早期表现出来，表明这些昼夜节律影响可能先于斑块的形成。APPswe/PS1dE9小鼠遗传模型可能有潜力作为理解AD中昼夜节律异常的神经病理学的工具，并作为测试这些症状的新型治疗药物的模型系统。
Background: In addition to cognitive decline, Alzheimer's Disease (AD) is also characterized by agitation and disruptions in activity and sleep. These symptoms typically occur in the evening or night and have been referred to as 'sundowning'. They are especially difficult for carers and there are no specific drug treatments. There is increasing evidence that these symptoms reflect pathology of circadian rhythm generation and transmission.Objective: We investigated whether a transgenic mouse model relevant to AD (APPswe/PS1dE9) exhibits circadian alterations in locomotor activity in their home cage and whether expression of clock genes involved in the regulation of the circadian cycle is abnormal in the hippocampus and medulla-pons brain regions isolated from these mice.Results: In 2month old female mice the APPswe/ PS1dE9 transgene alters levels and patterns in circadian rhythm of locomotor activity. Expression of the clock genes Per1, Per2, Cry1 and Cry2 was found to increase at night compared to day in wild-type control mice in the medulla/pons. This effect was blunted for Cry1 and Cry2 gene expression in APPswe/PS1dE9.Conclusion: This study suggests altered circadian regulation of locomotor activity is abnormal in female APPswe/PS1dE9 mice and that this alteration has biomolecular analogies in a widely available model of AD. The early age at which these effects are manifest suggests that these circadian effects may precede plaque development. The APPswe/PS1dE9 mouse genetic model may have potential to serve as a tool in understanding the neuropathology of circadian abnormalities in AD and as a model system to test novel therapeutic agents for these symptoms.