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.

阿尔茨海默病（AD）与大脑对葡萄糖的使用下降有关，葡萄糖是大脑最重要的燃料。星形胶质细胞在将葡萄糖从血流运送到脑组织深处的神经元活动单位所需的地方中起着关键作用。我们发现证据的缺陷，在一个关键的葡萄糖转运分子的星形胶质细胞在AD和小鼠线遗传修饰复制AD的某些方面。这种过度产生β-淀粉样肽（Aβ）的小鼠品系表现出循环葡萄糖调节异常，以及脑葡萄糖使用下降。这些影响与空间记忆测试中的不良表现相关。进一步模拟人类AD，小鼠在没有肥胖、高血糖、食欲破坏、身体活动变化、胰腺异常或胰岛素抵抗的情况下显示出这些问题。总之，这些发现激发了一种假设，即即使没有明显的AD，Aβ的水平也会在衰老的大脑中开始升高，它会干扰星形胶质细胞将外周葡萄糖带到神经元的能力，而神经元需要葡萄糖来增加与记忆和其他功能相关的神经活动。我们进一步提出，产品的载脂蛋白E基因的遗传变异称为ApoE 4有助于葡萄糖缺乏症，可能通过其对基因调控的影响。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ApoE的作用，特别是ApoE 4与特定DNA调控元件的相互作用，在葡萄糖转运的中断。最后，我们将利用校园内的药物发现资源，试图扭转葡萄糖调节失调。这些研究测试了一个关于AD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，该项目可能为治疗干预提供创新战略。 相关性 该项目的重点是阿尔茨海默氏症的风险因素对大脑能量利用的影响，如炎症和载脂蛋白E4。老年痴呆症涉及大脑葡萄糖输送的下降。这项研究将帮助我们了解阿尔茨海默病风险因素如何导致精神恶化的细节，并可能确定可以开发成治疗剂的化合物。