Effects of Altered Glucose Utilization on AB Levels and Functional Connectivity

改变葡萄糖利用对 AB 水平和功能连接的影响

• 批准号: 8636916
• 负责人: Shannon L Macauley-Rambach
• 金额: $ 5.7万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8636916
• 关键词: APP-PS1; Accounting; Acute; Affect; Age; Agonist; Alzheimer' s Disease; American; Amyloid; Amyloid beta-Protein; Bilateral; Biochemical; Blood Glucose; Brain; Brain region; Cerebrum; Characteristics; Chronic; Clinical; Data; Dementia; Deposition; Development; Diabetes Mellitus; Diazoxide; Disease Progression; Elderly; Electroencephalography; Epidemiologic Studies; Euglycemic Clamping; Generations; Genetic; Glucose; Glucose Clamp; Goals; Health Care Costs; Hippocampus (Brain); Hyperglycemia; Image; Impaired cognition; Insulin; Insulin Resistance; Intercellular Fluid; Link; Long-Term Effects; Mediating; Membrane Potentials; Metabolic Diseases; Metabolism; Microdialysis; Modeling; Monitor; Mus; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Optics; Oxygen Consumption; Pathogenesis; Pathology; Patients; Peptides; Positron-Emission Tomography; Potassium; Production; Relative (related person); Research; Risk; Role; Senile Plaques; Signal Transduction; Symptoms; Time; Work; aged; amyloid precursor protein processing; extracellular; glucose metabolism; glucose uptake; in vivo; in vivo imaging; interstitial; mouse model; neurochemistry; neuronal excitability; novel; peptide A; public health relevance; relating to nervous system; tau Proteins

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common form of dementia, affecting approximately 30 million people worldwide. Accumulation of the amyloid-¿ (A¿) peptide in the brain is hypothesized to be a key instigator in the pathogenesis of Alzheimer's disease (AD). Approximately 10-15 years prior to cognitive decline, aggregation of normally soluble monomeric A¿ accumulates into toxic forms, most notably amyloid plaques, within specific brain regions in the AD brain. Recent studies identified characteristics common to these AD prone regions including high neuronal activity, high functional connectivity, and high glucose utilization (relative to oxygen consumption). Interestingly, one of the first changes observed in the AD brain prior to or concurrent with clinical symptoms is aberrant glucose uptake. Furthermore, recent epidemiological studies suggest that patients with diabetes, a metabolic disorder characterized by chronic hyperglycemia, have a 2-4 increased risk for developing AD. Taken together, these observations implicate alterations in glucose metabolism in the disease progression of AD. Preliminary data suggests that a systemic increase in blood glucose levels results in a significant increase in A¿ production within the brain's interstitial fuid (ISF). Therefore, the goal of this proposal is to properly understand the relationship between aberrant glucose metabolism, neuronal activity, and functional connectivity as it relates to A¿ production and deposition in a mouse model of AD. By combining glucose clamps, to alter systemic blood glucose levels, with in vivo microdialysis, to ascertain the effects of systemic glucose modulation on the brain's neurochemistry, a direct understanding of how changes in blood glucose levels affect A¿ production and deposition, both acutely and chronically, can be achieved. Similarly, by monitoring neuronal activity via EEG recordings and functional connectivity via functional connectivity optical instrinsic signaling imaging (fcOIS), a better understanding of how increases in blood glucose levels and ISF A¿ affect these variables will be attained. Lastly, this proposal also seeks to identify the underlying mechanisms that cause alterations in blood glucose levels to result in increased A¿ levels. Thus, this proposal will help elucidate the role of glucose metabolism in AD pathogenesis as well as the link between AD and diabetes.

描述（由适用提供）：阿尔茨海默氏病（AD）是痴呆症的最常见形式，影响了全球约3000万人。假设淀粉样蛋白 - 肽的积累是在阿尔茨海默氏病（AD）发病机理中的关键刺激器。在认知能力下降之前大约10 - 15年，正常单体a的聚集在AD大脑的特定大脑区域内积聚成有毒形式，最著名的是淀粉样蛋白斑。最近的研究确定了这些容易发生区域常见的特征，包括高神经元活性，高功能连通性和高葡萄糖利用率（相对于氧气消耗）。有趣的是，在与临床症状并发之前，在AD大脑中观察到的第一个变化之一是葡萄糖摄取异常。此外，最近的流行病学研究表明，糖尿病患者是一种以慢性高血糖为特征的代谢疾病，其发展AD的风险增加了2-4。综上所述，这些观察结果在AD疾病进展中的葡萄糖代谢中的隐式改变。初步数据表明，血糖水平的系统性增加会导致大脑间质FUID（ISF）中A产生的显着增加。因此，该提案的目的是正确理解与AD小鼠模型中与A的生产和沉积有关的异常葡萄糖代谢，神经元活性和功能连通性之间的关系。通过将葡萄糖夹与体内微透析改变全身性血糖水平，以确定全身性葡萄糖调节对大脑神经化学的影响，直接了解血糖水平的变化如何急性和慢性地产生和沉积。同样，通过通过功能连通性光学信号成像（FCOIS）监测神经元活性和功能连接性，可以更好地理解血糖水平的增加，而ISF a已将附着这些变量。最后，该提案还试图确定导致血糖水平改变的基本机制，从而导致A水平升高。那，该提议将有所帮助 阐明葡萄糖代谢在AD发病机理以及AD和糖尿病之间的联系。