The metabolic interplay of sleep and Alzheimer's disease

项目摘要/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β蛋白(Aβ)和tau病理，反之，Aβ和tau聚集会扰乱睡眠。睡眠/醒来 周期是新陈代谢和神经元活动的主要调节器，其中日常活动的振荡与 Aβ和Tau的生产和清关。尽管调节神经元活动改变了睡眠/觉醒周期 和β/tau的释放，人们对糖代谢的波动如何导致睡眠和 阿尔茨海默病相关病理学。因此，这项提案的目标是确定是否会发生变化 代谢活动导致阿尔茨海默病患者神经元活动的变化从而扰乱睡眠，以及 代谢功能障碍可以作为挽救睡眠和阿尔茨海默病病理的新的治疗靶点。vbl.使用 结合脑电/肌电记录的海马体生物传感器，这项提议将调查血糖是如何 变异性和外周葡萄糖耐受影响睡眠和阿尔茨海默病啮齿动物模型 阿尔茨海默氏症相关病理。此外，我们将确定是否使外周血糖稳态正常化 通过糖尿病药物的治疗，二甲双胍足以维持和恢复睡眠结构 在阿尔茨海默病的背景下。

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.