Wu Meina, Zhou Fang, Cao Xiuli, Yang Junting, Bai Yu, Yan Xudong, Cao Jimin, Qi Jinshun
Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, 030001, China.
Department of Physiology, Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, 030001, China.
Neurosci Lett. 2018 May 29;676:13-18. doi: 10.1016/j.neulet.2018.04.008. Epub 2018 Apr 4.
Circadian rhythm disturbance (CRD) is one of the iconic manifestations in Alzheimer's disease (AD), a disease tightly associated with age, but the characteristics and gender difference of CRD occurred in AD have not been well demonstrated. Using 6-month-old triple transgenic AD mouse model (3xTg-AD) without obvious brain pathological changes, we demonstrated the gender difference of CRD at this age. We further showed abnormal Per gene expression in the central clock suprachiasmatic nucleus (SCN) of the 3xTg-AD mice. Specifically, compared with the wide type (WT) mice, the 3xTg-AD mice showed disrupted circadian locomotor rhythms both at LD (light-dark 12 h:12 h) and DD (constant dark) conditions, such as increased activities in the resting phase, decreased and scattered activities in the active phase, decreased overall activity intensities, amplitude, robustness, and increased intradaily variability. We further observed that 3xTg-AD female mice showed obviously less CRD compared with the 3xTg-AD male mice, and female mice of both WT and 3xTg-AD were more active in locomotor activity. Accordingly, 3xTg-AD mice showed a phase delay in the expression of Per1 and Per2 mRNA in the SCN, with the levels of Per1 and Per2 mRNA were significantly lower than that of WT mice at specific time points. We conclude that 3xTg-AD mice exhibit behavioral CRD at the age of six months with male gender preference, and these phenomena are at least partly associated with the alteration of Per1 and Per2 transcription patterns in the SCN.
昼夜节律紊乱（CRD）是阿尔茨海默病（AD）的标志性表现之一，AD是一种与年龄密切相关的疾病，但AD中发生的CRD的特征和性别差异尚未得到充分证实。我们使用6个月大且无明显脑病理变化的三转基因AD小鼠模型（3xTg-AD），证明了这个年龄段CRD的性别差异。我们进一步发现3xTg-AD小鼠的中枢生物钟视交叉上核（SCN）中Per基因表达异常。具体而言，与野生型（WT）小鼠相比，3xTg-AD小鼠在光暗周期（LD，12小时光照：12小时黑暗）和持续黑暗（DD）条件下的昼夜运动节律均被打乱，例如在休息期活动增加，在活动期活动减少且分散，整体活动强度、振幅、稳健性降低，日内变异性增加。我们进一步观察到，与3xTg-AD雄性小鼠相比，3xTg-AD雌性小鼠的CRD明显较少，并且WT和3xTg-AD的雌性小鼠在运动活动中更活跃。相应地，3xTg-AD小鼠SCN中Per1和Per2 mRNA的表达出现相位延迟，在特定时间点Per1和Per2 mRNA的水平显著低于WT小鼠。我们得出结论，3xTg-AD小鼠在6个月大时表现出行为性CRD，且具有雄性偏好，这些现象至少部分与SCN中Per1和Per2转录模式的改变有关。
