Supplementary Material for: Natural age-related slow-wave sleep alterations onset prematurely in the Tg2576 mouse model of Alzheimer’s disease

Introduction: Sleep insufficiency or decreased quality have been associated with Alzheimer’s disease (AD) already in its preclinical stages. Whether such traits are also present in rodent models of the disease has been poorly addressed, somewhat disabling the preclinical exploration of sleep-based therapeutic interventions for AD. Methods: We investigated age-dependent sleep-wake phenotype of a widely used mouse model of AD, the Tg2576 line. We implanted electroencephalography/ electromyography headpieces into 6 months old (plaque-free, n=10) and 11 months old (moderate plaque-burdened, n=10) Tg2576 and age-matched wild-type (WT, 6 month old n =10, 11 month old n =10) mice and recorded vigilance states for 24 hours. Results: Tg2576 mice exhibited significantly increased wakefulness and decreased non-rapid eye movement sleep over a 24-hour period compared to WT mice at 6, but not at 11 months of age. Concomitantly, power in the delta frequency was decreased in 6-month old Tg2576 mice in comparison to age-matched WT controls, rendering a reduced slow-wave energy phenotype in the young mutants. Lack of genotype-related differences over 24 hours in overall sleep-wake phenotype at 11 months of age appears to be the result of changes in sleep-wake characteristics accompanying the healthy aging of WT mice. Discussion/Conclusion: Therefore, our results indicate that at plaque-free disease stage, diminished sleep quality is present in Tg2576 mice which resembles aged healthy controls, suggesting an early-onset of sleep-wake deterioration in murine AD. Whether such disturbances in the natural patterns of sleep could in turn worsen disease progression warrants further exploration.

引言：睡眠不足或睡眠质量下降，已与阿尔茨海默病（Alzheimer’s disease, AD）的临床前阶段密切相关。目前针对该疾病啮齿类动物模型是否也存在此类特征的研究相对匮乏，这在一定程度上阻碍了基于睡眠的AD治疗干预手段的临床前探索。
方法：本研究针对一款广泛使用的AD小鼠模型——Tg2576品系，探究其年龄依赖性的睡眠-觉醒表型。我们将脑电图（electroencephalography, EEG）/肌电图（electromyography, EMG）头戴装置植入6月龄（无斑块沉积，n=10）与11月龄（存在中等程度斑块负荷，n=10）的Tg2576小鼠，以及同月龄野生型（wild-type, WT）小鼠（6月龄组n=10，11月龄组n=10），并连续24小时记录其睡眠-觉醒状态。
结果：与同月龄野生型小鼠相比，6月龄Tg2576小鼠在24小时内的觉醒时长显著增加，非快速眼动睡眠（non-rapid eye movement sleep, NREM sleep）时长显著减少，而11月龄小鼠未观察到此类基因型相关差异。与此同时，6月龄Tg2576小鼠的δ频段功率较同月龄野生型对照组下降，表现为年轻突变体的慢波能量表型减弱。11月龄小鼠未出现24小时睡眠-觉醒表型的基因型差异，这似乎源于野生型小鼠健康衰老过程中伴随的睡眠-觉醒特征改变。
讨论与结论：综上，本研究结果表明，在无斑块沉积的疾病早期阶段，Tg2576小鼠即存在睡眠质量下降的表型，该特征与老年健康对照组相似，提示小鼠AD模型的睡眠-觉醒功能衰退出现早于斑块沉积阶段。睡眠自然节律紊乱是否会进一步加重疾病进展，仍有待进一步探究。