Alzheimer’s disease (AD) patients exhibit memory disruptions and profound sleep disturbances, including disruption of deep non-rapid eye movement (NREM) sleep. Slow-wave activity (SWA) is a major restorative feature of NREM sleep and is important for memory consolidation. We generated a mouse model where GABAergic interneurons could be targeted in the presence of APPswe/PS1dE9 (APP) amyloidosis, APP-GAD-Cre mice. An electroencephalography (EEG) / electromyography (EMG) telemetry system was used to monitor sleep disruptions in these animals. Optogenetic stimulation of GABAergic interneurons in the anterior cortex targeted with channelrhodopsin-2 (ChR2) allowed us to examine the role GABAergic interneurons play in sleep deficits. We also examined the effect of optogenetic stimulation on amyloid plaques, neuronal calcium as well as sleep-dependent memory consolidation. In addition, microglial morphological features and functions were assessed using confocal microscopy and flow cytometry. Finally, we performed sleep deprivation during optogenetic stimulation to investigate whether sleep restoration was necessary to slow AD progression. APP-GAD-Cre mice exhibited impairments in sleep architecture including decreased time spent in NREM sleep, decreased delta power, and increased sleep fragmentation compared to nontransgenic (NTG) NTG-GAD-Cre mice. Optogenetic stimulation of cortical GABAergic interneurons increased SWA and rescued sleep impairments in APP-GAD-Cre animals. Furthermore, it slowed AD progression by reducing amyloid deposition, normalizing neuronal calcium homeostasis, and improving memory function. These changes were accompanied by increased numbers and a morphological transformation of microglia, elevated phagocytic marker expression, and enhanced amyloid β (Aβ) phagocytic activity of microglia. Sleep was necessary for amelioration of pathophysiological phenotypes in APP-GAD-Cre mice. In summary, our study shows that optogenetic targeting of GABAergic interneurons rescues sleep, which then ameliorates neuropathological as well as behavioral deficits by increasing clearance of Aβ by microglia in an AD mouse model.

中文翻译：

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通过光遗传学靶向 GABA 能神经元恢复睡眠可重新编程小胶质细胞并改善阿尔茨海默病模型中的病理表型

阿尔茨海默病 (AD) 患者表现出记忆障碍和严重的睡眠障碍，包括深度非快速眼动 (NREM) 睡眠的中断。慢波活动 (SWA) 是 NREM 睡眠的主要恢复特征，对于记忆巩固非常重要。我们建立了一个小鼠模型，在 APPswe/PS1dE9 (APP) 淀粉样变性 APP-GAD-Cre 小鼠存在的情况下，可以靶向 GABA 能中间神经元。使用脑电图（EEG）/肌电图（EMG）遥测系统来监测这些动物的睡眠中断。以通道视紫红质 2 (ChR2) 为靶点，对前皮质中的 GABA 能中间神经元进行光遗传学刺激，使我们能够研究 GABA 能中间神经元在睡眠缺陷中的作用。我们还研究了光遗传学刺激对淀粉样斑块、神经元钙以及睡眠依赖性记忆巩固的影响。此外，使用共聚焦显微镜和流式细胞术评估小胶质细胞的形态特征和功能。最后，我们在光遗传学刺激期间进行睡眠剥夺，以研究睡眠恢复对于减缓 AD 进展是否必要。与非转基因 (NTG) NTG-GAD-Cre 小鼠相比，APP-GAD-Cre 小鼠表现出睡眠结构损伤，包括 NREM 睡眠时间减少、Delta 功率降低和睡眠碎片化增加。皮质 GABA 能中间神经元的光遗传学刺激增加了 APP-GAD-Cre 动物的 SWA 并挽救了睡眠障碍。此外，它还通过减少淀粉样蛋白沉积、使神经元钙稳态正常化和改善记忆功能来减缓 AD 进展。这些变化伴随着小胶质细胞数量的增加和形态的转变、吞噬细胞标志物表达的升高以及小胶质细胞β淀粉样蛋白（Aβ）吞噬活性的增强。睡眠对于改善 APP-GAD-Cre 小鼠的病理生理表型是必要的。总之，我们的研究表明，GABA 能中间神经元的光遗传学靶向可以挽救睡眠，然后通过增加 AD 小鼠模型中小胶质细胞对 Aβ 的清除来改善神经病理学和行为缺陷。