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（由申请人提供）：阿尔茨海默病 (AD) 是最常见的痴呆症，影响全世界约 3000 万人。大脑中的 (A¿) 肽被认为是阿尔茨海默氏病 (AD) 发病机制的关键诱因，大约在认知能力下降之前 10-15 年，通常可溶性单体 A 的聚集。最近的研究发现，AD 大脑的特定脑区会积聚成有毒形式，最显着的是淀粉样蛋白斑块，这些特征包括高神经元活性、高功能连接性和高葡萄糖利用率（相对于耗氧量）。在出现临床症状之前或同时出现的 AD 大脑中首先观察到的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，患有糖尿病（一种以慢性高血糖为特征的代谢性疾病）的患者，患糖尿病的风险增加了 2-4 倍。综上所述，这些观察结果表明，AD 疾病进展过程中葡萄糖代谢发生了变化，初步数据表明，血糖水平的全身升高会导致 A¿因此，该提案的目标是正确理解异常葡萄糖代谢、神经活动和功能连接之间的关系，因为它与 A¿通过结合葡萄糖钳，改变全身血糖水平，与体内微透析相结合，确定全身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。影响A??类似地，通过脑电图记录监测神经活动，并通过功能连接光学本征信号成像（fcOIS）监测功能连接，可以实现急性和慢性的生产和沉积，从而更好地了解血糖水平和ISF A的增加。最后，该提案还试图确定导致血糖水平变化导致 A¿ 增加的潜在机制。因此，该建议将有所帮助。 阐明葡萄糖代谢在 AD 发病机制中的作用以及 AD 和糖尿病之间的联系。