Effects of Altered Glucose Utilization on AB Levels and Functional Connectivity

描述（由申请人提供）：阿尔茨海默病（AD）是最常见的痴呆症，影响全球约3000万人。淀粉样蛋白（A）肽在脑中的积累被假设为阿尔茨海默病（AD）发病机制的关键煽动者。在认知能力下降前约10-15年，正常可溶性单体A？的聚集在AD脑的特定脑区域内积累成毒性形式，最明显的是淀粉样斑块。最近的研究确定了这些AD易感区域的共同特征，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）。有趣的是，在临床症状之前或同时在AD脑中观察到的第一个变化之一是异常葡萄糖摄取。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紊乱）的患者具有增加2-4的发展成AD的风险。综上所述，这些观察结果暗示了AD疾病进展中葡萄糖代谢的改变。初步数据表明，血糖水平的全身性增加导致脑间质液（ISF）内A？产生的显著增加。因此，本提案的目标是正确理解异常葡萄糖代谢、神经元活性和功能连接之间的关系，因为它与AD小鼠模型中的A？产生和沉积有关。通过结合葡萄糖钳，以改变全身血糖水平，与体内微透析，以确定全身葡萄糖调节对大脑神经化学的影响，可以直接了解血糖水平的变化如何影响A？的产生和沉积，急性和慢性，可以实现。同样，通过EEG记录监测神经元活动，通过功能连接光学固有信号成像（fcOIS）监测功能连接，将更好地了解血糖水平和ISF A？的增加如何影响这些变量。最后，该提案还试图确定导致血糖水平改变导致A水平升高的潜在机制。因此，这项建议将有助于 阐明糖代谢在AD发病机制中的作用以及AD与糖尿病之间的联系。

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.