Role of glucose transport in Alzheimer's disease pathogenesis

阿尔茨海默病(AD)与大脑对葡萄糖的使用减少有关，葡萄糖是阿尔茨海默病最重要的燃料。星形胶质细胞在将葡萄糖从血液输送到大脑组织中更深层次的神经元活动单位所需的位置上发挥着关键作用。我们发现阿尔茨海默病患者星形胶质细胞的一个关键葡萄糖运输分子存在缺陷的证据，并在一种经过基因改造以复制阿尔茨海默病某些方面的小鼠品系中发现了缺陷。该小鼠系过度产生β-淀粉样多肽(Aβ)，表现出循环葡萄糖调节失调，以及大脑葡萄糖使用量下降。这些影响与空间记忆测试中的糟糕表现有关。进一步模仿人类AD，小鼠在没有肥胖、高血糖、食欲障碍、体力活动改变、胰腺异常或胰岛素抵抗的情况下表现出这些问题。总而言之，这些发现激发了一种假设，即Aβ的水平在老化的大脑中开始上升，即使在没有坦率的AD的情况下也是如此，它扰乱了星形胶质细胞将外周葡萄糖输送到神经元的能力，而神经元是与记忆和其他功能相关的神经活动增加所必需的。我们进一步提出，载脂蛋白E基因的一个基因变体ApoE4的产物可能通过影响基因调控而导致葡萄糖缺乏。这些想法将通过研究葡萄糖运输蛋白在阿尔茨海默病小鼠模型中的地位和功能来验证。首先，我们将评估星形胶质细胞和其他细胞类型以及炎症在这些事件中的相对作用。我们还将确定载脂蛋白E，特别是载脂蛋白E4‘S与特定的DNA调控元件相互作用在葡萄糖转运中断中的作用。最后，我们将利用校园药物发现资源，试图从药理学上逆转葡萄糖调节失调。这些研究测试了一种新的假说，即AD大脑中能量利用的特定元素及其与认知障碍的联系。因此，该项目可能为治疗干预提供创新的策略。 相关性 这个项目主要关注阿尔茨海默氏症的危险因素对大脑能量利用的影响，如炎症和载脂蛋白E4。阿尔茨海默氏症涉及到大脑葡萄糖供应的下降。这项研究将帮助我们了解阿尔茨海默氏症危险因素如何导致精神恶化的细节，并可能识别可以开发成治疗剂的化合物。

Alzheimer’s disease (AD) is associated with a decline in the brain’s use of glucose, its most important fuel. Astrocytes play a key role in shuttling glucose from the bloodstream to where it is needed by the neuronal units of activity deeper in the brain tissue. We find evidence of a defect in a key glucose transport molecule of astrocytes in AD and in a mouse line genetically modified to reproduce some aspects of AD. This mouse line, overproducing the β-amyloid peptide (Aβ), exhibits dysregulation of circulating glucose, as well as a decline in brain glucose use. These effects are correlated with poor performance in a test of spatial memory. Further mimicking human AD, the mice show these problems in the absence of obesity, hyperglycemia, disruption of appetite, changes in physical activity, pancreatic abnormality, or insulin resistance. Together, these findings inspire the hypothesis that Aβ, the levels of which begin to rise in the aging brain even without frank AD, perturbs the ability of astrocytes to bring peripheral glucose to neurons, where it is needed for the increased neurological activity associated with memory and other functions. We further propose that the product of a genetic variant of the apolipoprotein E gene known as ApoE4 contributes to the glucose deficiency, likely through its impact on gene regulation. These ideas will be tested through studies of the status and function of glucose transport proteins in the mouse model of AD. First, we will assess the relative roles of astrocytes and other cell types and inflammation in these events. We will also determine the role of ApoE, particularly that of ApoE4’s interaction with specific DNA regulatory elements, in the disruption of glucose transport. Finally, we will utilize on-campus drug-discovery resources in an attempt to reverse the glucose dysregulation pharmacologically. These studies test a novel hypothesis about a specific element of energy utilization in the AD brain and its connection to cognitive impairment. As such, the project may provide innovative strategies for therapeutic intervention. Relevance This project focuses on the impact made on brain energy utilization by risk factors for Alzheimer’s such as inflammation and apolipoprotien E4. Alzheimer’s involves a drop in brain glucose delivery. This study will help us understand details about how Alzheimer risk factors bring about mental deterioration, and it may identify chemical compounds that can be developed into therapeutic agents.