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

慢波活动作为阿尔茨海默病神经变性进展的调节剂

• 批准号: 10657937
• 负责人: Brian J Bacskai
• 金额: $ 127.22万
• 依托单位: BOSTON VA RESEARCH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10657937
• 关键词: Slow; wave; activity; modifier; progression

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.

睡眠-觉醒中断和认知障碍是阿尔茨海默病的普遍现象和致残特征 (AD) 患者表现出严重的睡眠障碍，包括非快速眼动 (NREM) 中断。 NREM 睡眠的一个主要恢复特征是，它也与正常的认知功能有关。 慢波活动 (SWA) 最近的研究结果表明 SWA 生成受损之间存在因果关系。 睡眠期间和 AD 发病机制包括淀粉样蛋白-β (Aβ) 肽的细胞外积累和 虽然有证据表明皮质-丘脑环路调节 SWA，但确切的细胞功能障碍。 AD 中 SWA 受损的分子机制尚不清楚，因此需要对细胞进行表征。 和负责 SWA 生成的分子机制，以减少 SWA 和 我们提出的研究将阐明 SWA 的睡眠状态相关机制。 使用 AD 动物模型进行的研究表明，抑制性神经传递受损。 该提案的总体目标是确定和激励特定的 SWA。 调节中间神经元以确定哪些细胞恢复 SWA 并使用 在此，我们建议采用光遗传学和化学遗传学来控制AD小鼠模型。 神经元回路旨在恢复 SWA 并减缓 AD 进展，因此，我们的研究结果将决定细胞。 睡眠与 AD 之间的分子关系，以及特定时期的中间神经元的靶向 睡眠作为一种新颖的治疗方法。