The metabolic interplay of sleep and Alzheimer's disease

睡眠与阿尔茨海默病的代谢相互作用

基本信息

批准号：
10398178
负责人：
Shannon L Macauley-Rambach
金额：
$ 70.6万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10398178
关键词：
Abeta clearance Acute Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid beta-Protein Biosensor Blood Glucose Brain Cause of Death Cerebrum Chronic Coupled Electroencephalography Glucose Glucose Intolerance Goals Hippocampus (Brain)Human Hyperglycemia Hypoglycemia Impairment Individual Insulin Resistance Intervention Lead Maintenance Measures Metabolic Metabolic dysfunction Metabolism Metformin Modeling Mus Nerve Degeneration Neurons Pathogenesis Pathology Peripheral Pharmaceutical Preparations Pharmacological Treatment Pharmacology Process Production Rodent Model Role Sleep Sleep Architecture Sleep Deprivation Sleep Disorders Sleep Wake Cycle Sleep disturbances United States Wakefulness Wild Type Mouse Work abeta accumulation blood glucose regulation diabetic euglycemia glucose metabolism glucose tolerance mouse model neuronal metabolism new therapeutic target novel preservation prevent response restoration tau Proteins tau aggregation tau function

项目摘要

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.

项目摘要/摘要阿尔茨海默氏病与睡眠之间存在双向关系淀粉样蛋白β（Aβ）和tau病理学，相反，Aβ和TAU聚集破坏了睡眠。睡眠/唤醒循环是代谢和神经元活动的主要调节剂，该活动的每日振荡与 Aβ和TAU的生产和清除。尽管调节神经元活动会改变两者的睡眠/唤醒周期和Aβ/tau释放，对葡萄糖代谢中的波动如何驱动睡眠变化和阿尔茨海默氏病有关的病理学。因此，该提案的目的是确定是否发生变化代谢活性导致神经元活性的变化，以破坏阿尔茨海默氏病的睡眠，以及是否是否代谢功能障碍可以作为营救睡眠和阿尔茨海默氏病病理学的新型热靶标。使用海马生物传感器以及EEG/EMG记录，该建议将研究血糖如何在啮齿动物模型中，可变性和外周葡萄糖肠道影响睡眠和阿尔茨海默氏病阿尔茨海默氏症的相关病理。此外，我们将确定是否将外周葡萄糖稳态标准化通过用糖尿病药物治疗，二甲双胍足以保存和恢复睡眠结构在阿尔茨海默氏病的情况下。