Van Erum Jan, Van Dam Debby, Sheorajpanday Rishi, De Deyn Peter Paul
Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, Department of Biomedical Sciences, University of Antwerp, Wilrijk (Antwerp), Belgium.
Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, Department of Biomedical Sciences, University of Antwerp, Wilrijk (Antwerp), Belgium; Department of Neurology and Alzheimer Center, University of Groningen and University Medical Center Groningen (UMCG), Groningen, the Netherlands.
Behav Brain Res. 2019 Nov 5;373:112089. doi: 10.1016/j.bbr.2019.112089. Epub 2019 Jul 17.
Alzheimer's disease (AD), which accounts for most of the dementia cases, is, aside from cognitive deterioration, often characterized by the presence of non-cognitive symptoms such as activity and sleep disturbances. AD patients typically experience increased sleep fragmentation, excessive daytime sleepiness and night-time insomnia. Here, we sought to investigate the link between sleep architecture, cognition and amyloid pathology in the APP23 amyloidosis mouse model for AD. By means of polysomnographic recordings the sleep-wake cycle of freely-moving APP23 and wild-type (WT) littermates of 3, 6 and 12 months of age was examined. In addition, ambulatory cage activity was assessed by interruption of infrared beams surrounding the home cage. To assess visuo-spatial learning and memory a hidden-platform Morris-type Water Maze (MWM) experiment was performed. We found that sleep architecture is only slightly altered at early stages of pathology, but significantly deteriorates from 12 months of age, when amyloid plaques become diffusely present. APP23 mice of 12 months old had quantitative reductions of NREM and REM sleep and were more awake during the dark phase compared to WT littermates. These findings were confirmed by increased ambulatory cage activity during that phase of the light-dark cycle. No quantitative differences in sleep parameters were observed during the light phase. However, during this light phase, the sleep pattern of APP23 mice was more fragmented from 6 months of age, the point at which also cognitive abilities started to be affected in the MWM. Sleep time also positively correlated with MWM performance. We also found that spectral components in the EEG started to alter at the age of 6 months. To conclude, our results indicate that sleep architectural changes arise around the time the first amyloid plaques start to form and cognitive deterioration becomes apparent. These changes start subtle, but gradually worsen with age, adequately mimicking the clinical condition.
阿尔茨海默病（AD）占大多数痴呆病例，除认知功能衰退外，通常还具有非认知症状，如活动和睡眠障碍。AD患者通常会出现睡眠碎片化增加、日间过度嗜睡和夜间失眠。在此，我们试图研究AD的APP23淀粉样变性小鼠模型中睡眠结构、认知与淀粉样蛋白病理学之间的联系。通过多导睡眠图记录，对3、6和12月龄的自由活动的APP23小鼠及其野生型（WT）同窝小鼠的睡眠-觉醒周期进行了检查。此外，通过中断围绕饲养笼的红外光束来评估笼内活动。为了评估视觉空间学习和记忆，进行了一项隐藏平台莫里斯型水迷宫（MWM）实验。我们发现，在病理学早期睡眠结构仅略有改变，但从12月龄开始显著恶化，此时淀粉样斑块开始广泛出现。与WT同窝小鼠相比，12月龄的APP23小鼠非快速眼动（NREM）睡眠和快速眼动（REM）睡眠在数量上减少，并且在黑暗阶段更清醒。在明暗周期的该阶段笼内活动增加证实了这些发现。在光照阶段未观察到睡眠参数的数量差异。然而，在这个光照阶段，APP23小鼠的睡眠模式从6月龄开始更加碎片化，此时在MWM中认知能力也开始受到影响。睡眠时间也与MWM表现呈正相关。我们还发现脑电图（EEG）的频谱成分在6月龄时开始改变。总之，我们的结果表明，睡眠结构变化出现在首批淀粉样斑块开始形成且认知衰退变得明显之时。这些变化开始时很细微，但随着年龄增长逐渐恶化，充分模拟了临床情况。
