Eli Lilly and Company, Erl Wood Manor, Windlesham, Surrey, GU20 6PH, UK.
Alzheimers Res Ther. 2020 Jul 15;12(1):84. doi: 10.1186/s13195-020-00651-0.
Disturbed sleep is associated with cognitive decline in neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). The progressive sequence of how neurodegeneration affects aspects of sleep architecture in conjunction with behavioural changes is not well understood.
We investigated changes in sleep architecture, spectral power and circadian rhythmicity in the tet-off rTg4510 mouse overexpressing human P301L tau within the same subjects over time. Doxycycline-induced transgene-suppressed rTg4510 mice, tTa carriers and wild-type mice were used as comparators. Spectral power and sleep stages were measured from within the home cage environment using EEG electrodes. In addition, locomotor activity and performance during a T-maze task were measured.
Spectral power in the delta and theta bands showed a time-dependent decrease in rTg4510 mice compared to all other groups. After the initial changes in spectral power, wake during the dark period increased whereas NREM and number of REM sleep bouts decreased in rTg4510 compared to wild-type mice. Home cage locomotor activity in the dark phase significantly increased in rTg4510 compared to wild-type mice by 40 weeks of age. Peak-to-peak circadian rhythm amplitude and performance in the T-maze was impaired throughout the experiment independent of time. At 46 weeks, rTG4510 mice had significant degeneration in the hippocampus and cortex whereas doxycycline-treated rTG4510 mice were protected. Pathology significantly correlated with sleep and EEG outcomes, in addition to locomotor and cognitive measures.
We show that reduced EEG spectral power precedes reductions in sleep and home cage locomotor activity in a mouse model of tauopathy. The data shows increasing mutant tau changes sleep architecture, EEG properties, behaviour and cognition, which suggest tau-related effects on sleep architecture in patients with neurodegenerative diseases.
睡眠障碍与神经退行性疾病（如阿尔茨海默病[AD]和额颞叶痴呆[FTD]）的认知能力下降有关。神经退行性变如何影响睡眠结构的各个方面以及行为变化的渐进序列尚不清楚。
我们在同一研究对象中随时间研究了过度表达人类 P301L tau 的 tet-off rTg4510 小鼠的睡眠结构、频谱功率和昼夜节律变化。使用多西环素诱导的转基因抑制 rTg4510 小鼠、tTa 载体和野生型小鼠作为对照。使用 EEG 电极在家庭笼环境中测量频谱功率和睡眠阶段。此外，还测量了 T 迷宫任务期间的运动活动和表现。
与所有其他组相比，rTg4510 小鼠的 delta 和 theta 频段的频谱功率呈现时间依赖性下降。在频谱功率发生最初变化后，rTg4510 小鼠在暗期的觉醒增加，而与野生型小鼠相比，非快速眼动（NREM）和 REM 睡眠次数减少。rTg4510 小鼠在暗期的家庭笼运动活动与野生型小鼠相比，在 40 周龄时显著增加。整个实验过程中，T 迷宫的峰值到峰值昼夜节律幅度和表现均受损，与时间无关。在 46 周时，rTG4510 小鼠的海马体和皮层出现明显退化，而多西环素处理的 rTG4510 小鼠则受到保护。病理学与睡眠和 EEG 结果以及运动和认知测量显著相关。
我们表明，tau 病变小鼠模型中脑电图（EEG）频谱功率降低先于睡眠和家庭笼运动活动减少。该数据表明，突变 tau 的增加会改变睡眠结构、EEG 特性、行为和认知，这表明 tau 对神经退行性疾病患者的睡眠结构有影响。
