Role of glucose transport in Alzheimer's disease pathogenesis

葡萄糖转运在阿尔茨海默病发病机制中的作用

• 批准号: 10768392
• 负责人: Steven W Barger
• 金额: $ 38.25万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10768392
• 关键词: Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid beta-Protein; Apolipoprotein E; Astrocytes; Blood Circulation; Brain; Chemicals; DNA; Defect; Desire for food; Deterioration; Drops; Elements; Event; Exhibits; Gene Expression Regulation; Genes; Glucose; Glucose Transporter; Human; Hyperglycemia; Impaired cognition; Inflammation; Insulin Resistance; Memory; Mus; Neurologic; Neurons; Obesity; Pancreas; Pathogenesis; Performance; Peripheral; Physical activity; Play; Psyche structure; Regulatory Element; Resources; Role; Testing; Therapeutic Agents; Therapeutic Intervention; aging brain; apolipoprotein E-4; brain tissue; cell type; drug discovery; genetic variant; glucose transport; innovation; mouse model; novel; pharmacologic; spatial memory

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.

阿尔茨海默氏病（AD）与大脑使用葡萄糖（其最重要的燃料）的使用下降有关。星形胶质细胞在将葡萄糖从血液中延伸到需要的神经元单位所需的位置中起着关键作用。我们发现，AD中星形胶质细胞的关键葡萄糖转运分子和经过基因修饰的小鼠系中的缺陷的证据，以重现AD的某些方面。该小鼠系过量产生的β-淀粉样肽（Aβ）表现出循环葡萄糖的失调以及脑葡萄糖使用的下降。这些效果与空间记忆测试中的性能差有关。进一步模仿人类广告，在没有肥胖症，高血糖，食欲中断，体育活动的变化，胰腺异常或胰岛素抵抗的情况下，小鼠显示了这些问题。总之，这些发现激发了以下假设：Aβ即使没有弗兰克AD，即使没有Frank AD的Aβ也开始升高，即使存在星形胶质细胞将周围葡萄糖带到神经元的能力，而神经元与记忆和其他功能相关的神经系统活性增加了。我们进一步建议，称为APOE4的载脂蛋白E基因的遗传变异产物有助于葡萄糖缺乏，这可能是由于其对基因调节的影响。这些想法将通过研究AD小鼠模型中葡萄糖转运蛋白的状态和功能的研究来测试。首先，我们将评估星形胶质细胞和其他细胞类型的相对作用以及在这些事件中的炎症。我们还将确定APOE的作用，尤其是APOE4与特定DNA调节元件的相互作用在葡萄糖转运破坏中的作用。最后，我们将利用校园药物发现资源，以试图以药物为葡萄糖失调。这些研究检验了一个关于广告大脑中能量利用的特定元素及其与认知障碍的联系的新假设。因此，该项目可以为治疗干预提供创新的策略。 关联 该项目的重点是风险因素对阿尔茨海默氏症（例如感染和apolipoprotien e4）对脑能量利用的影响。阿尔茨海默氏症涉及大脑葡萄糖递送的下降。这项研究将帮助我们了解有关阿尔茨海默氏症风险因素如何带来心理定义的详细信息，并且可以鉴定可以发展为治疗剂的化学化合物。