Slow-wave activity as a modifier of the progression of neurodegeneration in Alzheimer's disease

睡眠-觉醒中断和认知障碍是阿尔茨海默病的普遍和致残特征 （AD）。AD患者表现出严重的睡眠障碍，包括非快速眼动（NREM）中断 睡吧NREM睡眠的一个主要恢复特征，也与适当的认知功能有关， 慢波活动（SWA）。最近的研究结果表明，SWA的产生受损之间存在因果关系， 在睡眠和AD发病机制，包括细胞外积累的淀粉样β（Aβ）肽， 神经元功能障碍虽然有证据表明，皮质-丘脑回路调节SWA，但确切的细胞调节机制是， AD中SWA受损的分子机制尚不清楚。因此，需要表征细胞 以及负责SWA生成以减少SWA中的损伤的分子机制， AD的发病机制我们提出的研究将阐明睡眠状态相关的机制，其中SWA 保护AD。使用AD动物模型的研究表明，抑制性神经传递受损 在SWA期间。本提案的总体目标是确定和激励具体的SWA 调节神经元间，以确定哪些细胞恢复SWA并减轻AD相关的病理， 建立AD小鼠模型。在此，我们建议采用光遗传学和化学遗传学来控制， 神经元回路旨在恢复SWA和减缓AD进展。因此，我们的研究结果将确定细胞 以及睡眠和AD之间的分子关系，在特定的睡眠期间靶向中间神经元。 睡眠作为一种新的治疗方法。

Sleep-wake disruptions and cognitive impairments are prevalent and disabling features of Alzheimer's disease (AD). AD patients exhibit profound sleep disturbances including disruption of non-rapid eye movement (NREM) sleep. A major restorative feature of NREM sleep, which is also associated with proper cognitive functioning, is slow-wave activity (SWA). Recent findings suggest a causal relationship between impaired generation of SWA during sleep and AD pathogenesis including extracellular accumulation of the amyloid-β (Aβ) peptide and neuronal dysfunction. While evidence indicates that cortical-thalamic loops regulate SWA, the exact cellular and molecular mechanisms for impaired SWA in AD are unknown. Thus, a need exists to characterize the cells and molecular mechanisms responsible for SWA generation to reduce the impairments in SWA and pathogenesis of AD. We propose studies that will elucidate the sleep state related mechanisms by which SWA protects against AD. Studies using AD animal models suggest that inhibitory neurotransmission is impaired during periods of SWA. The overall objective of this proposal is to identify and stimulate specific SWA modulating interneuronals to determine which cells restore SWA and mitigate AD-related pathology using an established AD mouse model. Herein, we propose to employ optogenetics and chemogenetics to control neuronal circuits aimed to restore SWA and slow AD progression. Thus, our findings will determine the cellular and molecular relationships between sleep and AD, with the targeting of interneurons during specific periods of sleep as a novel therapeutic approach.