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.

项目概要/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 β 淀粉样蛋白 (Aβ) 和 tau 蛋白病理学，相反，Aβ 和 tau 蛋白聚集会扰乱睡眠/觉醒。周期是代谢和神经活动的主要调节器，每日活动的波动与尽管调节神经活动会改变睡眠/觉醒周期，但 Aβ 和 tau 的产生和清除。和 Aβ/tau 释放，但人们对葡萄糖代谢的波动如何驱动睡眠和睡眠的变化知之甚少。因此，该提案的目标是确定阿尔茨海默病相关病理学是否发生变化。代谢活动会导致神经活动发生变化，从而扰乱阿尔茨海默病患者的睡眠，以及是否代谢功能障碍可以作为拯救睡眠和阿尔茨海默病病理的新治疗靶点。海马生物传感器与脑电图/肌电图记录相结合，该提案将研究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的睡眠和阿尔茨海默病此外，我们将确定是否使外周葡萄糖稳态正常化。通过糖尿病药物二甲双胍治疗足以维持和恢复睡眠结构在阿尔茨海默病的情况下。