Interactions between metabolism and sleep in Alzheimer's disease pathogenesis

阿尔茨海默病发病机制中新陈代谢和睡眠之间的相互作用

• 批准号: 10327600
• 负责人: Caitlin Margaret Carroll
• 金额: $ 4.6万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-05 至 2023-08-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10327600
• 关键词: Abeta synthesis; Acute; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease pathology; American; Amyloid; Amyloid beta-Protein; Automobile Driving; Biosensor; Blood Glucose; Caring; Cerebrum; Characteristics; Chronic; Dementia; Deposition; Development; Diabetes Mellitus; Disease; Diurnal Rhythm; Electroencephalography; Event; Functional disorder; Genetic Models; Glucose; Glucose Intolerance; Goals; Grant; Hippocampus (Brain); Hyperglycemia; Hypoglycemia; Impairment; Implant; Incidence; Individual; Intercellular Fluid; Measures; Medical; Metabolic; Metabolic dysfunction; Metabolism; Modeling; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity Epidemic; Pathogenesis; Pathogenicity; Pathology; Peripheral; Population; Prevalence; Process; Risk; Risk Factors; Senile Plaques; Sleep; Sleep Deprivation; Sleep Fragmentations; Sleep Wake Cycle; Sleep disturbances; Symptoms; Tauopathies; Training; United States; Wakefulness; cost; experience; extracellular; glucose metabolism; glucose tolerance; hypocretin; mouse model; peripheral blood; receptor; response; side effect; tau Proteins; tau aggregation; therapeutic target

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease is the most common form of dementia, affecting over 45 million people worldwide and costing over $800 billion in medical care. It is characterized by the accumulation of extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tau tangles, which occur 5 to 15 years before symptom onset. Metabolic perturbation and sleep disturbance are key features of Alzheimer’s disease, where they represent both cause and consequence of disease pathophysiology. A bidirectional relationship exists between the two where impaired sleep and metabolism individually contribute to Alzheimer’s disease development while the presence of pathology leads to decreased cerebral metabolism, peripheral glucose intolerance, and disrupted sleep. Further, individuals with type-2-diabetes (T2D) have a 2-4-fold increased risk of developing Alzheimer’s disease, suggesting an underlying common mechanism. Chronic hyperglycemia, a defining characteristic of T2D, leads to increased neuronal activity and Aβ levels within the hippocampus, an effect exacerbated by the presence of Aβ pathology, indicating a relationship between peripheral metabolism, neuronal activity, and Aβ production that is compromised by plaque pathology. These metrics all have diurnal rhythms maintained by the sleep/wake cycle; therefore, acute changes in peripheral blood glucose levels, or glycemic variability, may be sufficient to drive sleep disruptions and further peripheral metabolic dysfunction by modifying the relationship between cerebral glucose metabolism and neuronal activity. The purpose of the training grant is to determine how acute glycemic variability, common in both the development and treatment of T2D, synergizes with Alzheimer’s disease pathology to affect cerebral metabolism, neuronal activity, and sleep/wake cycles. We will directly evaluate the impact of peripheral glycemic challenges using biosensors implanted into the hippocampus of mice measuring changes in interstitial fluid (ISF) glucose and lactate levels, measures of cerebral metabolism and neuronal activity, respectively. We will determine the impact of glycemic variability on sleep/wake cycles through simultaneous EEG/EMG recordings, evaluating both the total duration in each state as well as sleep fragmentation. Finally, we will characterize baseline peripheral metabolism of the genetic model mice and determine the effect of sleep deprivation and sleep rescue on peripheral glucose tolerance. Together, this proposal will establish glycemic variability as mechanism driving decreased sleep, increased cerebral metabolism and neuronal activity, and further peripheral glucose intolerance, all of which are well established risk-factors in the development of Alzheimer’s disease. Defining these relationships will offer a more efficacious approach to targeting the interactions between T2D and Alzheimer’s disease.

项目总结/文摘