The metabolic interplay of sleep and Alzheimer's disease

项目总结/摘要 阿尔茨海默病和睡眠之间存在双向关系，睡眠中断会增加 淀粉样蛋白β（Aβ）和tau病理学，相反，Aβ和tau聚集破坏睡眠。睡眠/唤醒 周期是代谢和神经元活动的主要调节器，其中活动的每日振荡与 Aβ和tau的产生和清除。虽然调节神经元活动会改变睡眠/觉醒周期， 和Aβ/tau蛋白的释放，对葡萄糖代谢的波动如何驱动睡眠的变化知之甚少， 阿尔茨海默病相关的病理学。因此，本提案的目标是确定是否有变化， 代谢活动导致神经元活动的变化，破坏阿尔茨海默病的睡眠， 代谢功能障碍可以作为一个新的治疗目标，以挽救睡眠和阿尔茨海默氏症的病理。使用 海马生物传感器加上EEG/EMG记录，这项建议将调查血糖如何 变异性和外周葡萄糖耐受不良影响啮齿动物模型睡眠和阿尔茨海默病 阿尔茨海默病相关的病理学。此外，我们将确定是否正常化外周葡萄糖稳态， 通过使用糖尿病药物二甲双胍治疗，足以保持和恢复睡眠结构 在老年痴呆症的背景下。

PROJECT SUMMARY/ABSTRACT A bidirectional relationship exists between Alzheimer’s disease and sleep, where disrupted sleep increases amyloid-beta (Aβ) and tau pathology and conversely, Aβ and tau aggregation disrupt sleep. The sleep/wake cycle is a master regulator of metabolic and neuronal activity, where daily oscillations in activity are coupled to the production and clearance of Aβ and tau. Although modulating neuronal activity alters both sleep/wake cycles and Aβ/tau release, less is known about how fluctuations in glucose metabolism drive changes in sleep and Alzheimer’s disease related pathology. Therefore, the goal of this proposal is to determine whether changes in metabolic activity lead to changes in neuronal activity to disrupt sleep in Alzheimer’s disease and whether metabolic dysfunction can serve as a novel therapeutic target to rescue sleep and Alzheimer’s pathology. Using hippocampal biosensors coupled with EEG/EMG recordings, this proposal will investigate how glycemic variability and peripheral glucose intolerance affect sleep and Alzheimer’s disease in rodent models of Alzheimer’s related pathology. Moreover, we will establish whether normalizing peripheral glucose homeostasis through treatment with the diabetic medication, metformin, is sufficient to preserve and restore sleep architecture in the setting of Alzheimer’s disease.