Berg Monica van den, Heymans Loran, Toen Daniëlle, Adhikari Mohit A, Audekerke Johan Van, Verschuuren Marlies, Pintelon Isabel, Vos Winnok H De, Linden Annemie Van der, Verhoye Marleen, Keliris Georgios A
Bio-Imaging Lab, University of Antwerp, Campus Drie Eiken - Building UC, Universiteitsplein 1, Wilrijk, 2610, Belgium.
µNEURO Research Centre of Excellence, University of Antwerp, Antwerp, Belgium.
Acta Neuropathol Commun. 2025 May 10;13(1):96. doi: 10.1186/s40478-025-02016-w.
Sleep alterations are known to occur in Alzheimer's disease (AD), before cognitive symptoms become apparent, and are thought to play an important role in the pathophysiology of AD. However, knowledge on the extent of macro- and microstructural changes of sleep during early, presymptomatic stages of AD is limited. We hypothesize that Aβ-induced perturbations of neuronal activity disrupt this oscillatory activity during sleep at pre-plaque stages of AD. In this study, we aimed to assess hippocampal oscillatory activity during sleep at pre- and early-plaque stages of AD, by performing 24-hour hippocampal electrophysiological measurements in TgF344-AD rats and wildtype littermates at pre- and early-plaque stages of AD. To provide a mechanistic understanding, histological analysis was performed to quantify GABA-ergic, glutamatergic and cholinergic synapses. We observed a differential impact of AD on hippocampal activity during rapid eye movement (REM) and non-REM (NREM) sleep, in the absence of robust changes in circadian rhythm. TgF344-AD rats demonstrated increased duration of sharp wave-ripples during NREM sleep, irrespective of age. Interestingly, a significantly decreased theta-gamma coupling was observed in TgF344-AD rats, prior to amyloid plaque deposition, which was partially restored at the early-plaque stage. The partial recovery of hippocampal activity during REM sleep coincided with an increased number of cholinergic synapses in the hippocampus during the early-plaque stage in TgF344-AD rats, suggestive of basal forebrain cholinergic compensation mechanisms. The results from this study reveal early changes in hippocampal activity prior to Aβ plaque deposition in AD. In addition, the current findings imply an important role of the cholinergic system to compensate for AD-related network alterations, thereby partially restoring sleep architecture and hippocampal activity.
已知在阿尔茨海默病（AD）中，认知症状出现之前就会发生睡眠改变，并且睡眠改变被认为在AD的病理生理学中起重要作用。然而，关于AD早期症状前阶段睡眠的宏观和微观结构变化程度的了解有限。我们假设，在AD的斑块前阶段，Aβ诱导的神经元活动扰动会破坏睡眠期间的这种振荡活动。在本研究中，我们旨在通过对处于AD斑块前和早期阶段的TgF344-AD大鼠和野生型同窝仔鼠进行24小时海马电生理测量，来评估AD斑块前和早期阶段睡眠期间的海马振荡活动。为了提供机制性理解，进行了组织学分析以量化GABA能、谷氨酸能和胆碱能突触。我们观察到，在昼夜节律没有明显变化的情况下，AD对快速眼动（REM）睡眠和非快速眼动（NREM）睡眠期间的海马活动有不同影响。TgF344-AD大鼠在NREM睡眠期间的尖波涟漪持续时间增加，与年龄无关。有趣的是，在淀粉样斑块沉积之前，TgF344-AD大鼠的θ-γ耦合显著降低，在斑块早期阶段部分恢复。TgF344-AD大鼠在REM睡眠期间海马活动的部分恢复与斑块早期阶段海马中胆碱能突触数量的增加相一致提示了基底前脑胆碱能补偿机制。本研究结果揭示了AD中Aβ斑块沉积之前海马活动的早期变化。此外，目前的研究结果暗示胆碱能系统在补偿AD相关网络改变方面具有重要作用，从而部分恢复睡眠结构和海马活动。
