Liu Shunjie, Liu Xingyi, Ke Man, Wang Jinliang
Department of Neurology, The Second People's Hospital of Foshan, Foshan 528000, Guangdong Province, China.
Department of Neurology, The Second People's Hospital of Foshan, Foshan 528000, Guangdong Province, China.
Exp Neurol. 2025 Apr;386:115153. doi: 10.1016/j.expneurol.2025.115153. Epub 2025 Jan 18.
A large proportion of Alzheimer's disease (AD) patients suffer from various types of chronic sleep disturbances, including sleep fragmentation (SF). In addition, impaired mitochondrial biogenesis is an important feature of AD, but whether it is altered in sleep disorders has not been fully elucidated. Hence, we aimed to investigate the relationship between SF and mitochondrial biogenesis and the possible impact of SF on AD-related pathology. In this study, thirty-six 9-month-old 3xTgAD model mice and thirty-six 9-month-old wild-type (WT) C57BL/6 J mice were divided into a control group (6 weeks of normal sleep), a SF group (6 weeks of SF) and a SF + recovery sleep group (6 weeks of SF followed by 2 weeks of recovery sleep). Cognitive functions were assessed by behavioural experiments. Mitochondrial structure and function and the activity of a classic mitochondrial biogenesis signalling pathway were investigated using transmission electron microscopy (TEM), reverse transcription quantitative polymerase chain reaction (RT-qPCR), immunofluorescence and Western blotting. Markers of AD-related pathology, including the levels of amyloid β (Aβ) and tau proteins, were assessed by immunofluorescence and Western blotting. The expression of insulin-degrading enzyme (IDE) was assessed by Western blotting. We found that long-term SF impaired the cognitive functions of the mice. In addition, chronic SF reduced the expression of mitochondrial respiratory chain components, the number of mitochondria, the fluorescence intensity of COX-IV, the level of mitochondrial DNA (mtDNA) and the expression of crucial regulators of the AMPK/SIRT-1/PGC-1α signalling pathway in the mouse prefrontal cortex and hippocampus, while recovery sleep could partly abrogate these effects. Moreover, SF reduced the protein level of IDE and increased the Aβ burden and tau hyperphosphorylation. This study demonstrates that chronic SF can negatively regulate the AMPK/SIRT-1/PGC-1α signalling pathway to disrupt mitochondrial biogenesis in the brains of mice, which may subsequently exacerbate AD-related pathology by decreasing the expression of IDE.
很大一部分阿尔茨海默病（AD）患者患有各种类型的慢性睡眠障碍，包括睡眠片段化（SF）。此外，线粒体生物合成受损是AD的一个重要特征，但它在睡眠障碍中是否发生改变尚未完全阐明。因此，我们旨在研究睡眠片段化与线粒体生物合成之间的关系以及睡眠片段化对AD相关病理的可能影响。在本研究中，将36只9月龄的3xTgAD模型小鼠和36只9月龄的野生型（WT）C57BL/6 J小鼠分为对照组（正常睡眠6周）、睡眠片段化组（睡眠片段化6周）和睡眠片段化+恢复睡眠组（睡眠片段化6周，随后恢复睡眠2周）。通过行为实验评估认知功能。使用透射电子显微镜（TEM）、逆转录定量聚合酶链反应（RT-qPCR）、免疫荧光和蛋白质印迹法研究线粒体结构和功能以及经典线粒体生物合成信号通路的活性。通过免疫荧光和蛋白质印迹法评估AD相关病理标志物，包括淀粉样β（Aβ）和tau蛋白水平。通过蛋白质印迹法评估胰岛素降解酶（IDE）的表达。我们发现长期睡眠片段化损害了小鼠的认知功能。此外，慢性睡眠片段化降低了小鼠前额叶皮质和海马体中线粒体呼吸链成分的表达、线粒体数量、COX-IV的荧光强度、线粒体DNA（mtDNA）水平以及AMPK/SIRT-1/PGC-1α信号通路关键调节因子的表达，而恢复睡眠可以部分消除这些影响。此外，睡眠片段化降低了IDE的蛋白水平，增加了Aβ负担和tau过度磷酸化。本研究表明，慢性睡眠片段化可负向调节AMPK/SIRT-1/PGC-1α信号通路，破坏小鼠大脑中的线粒体生物合成，这随后可能通过降低IDE的表达而加剧AD相关病理。
