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) 与大脑对葡萄糖的利用减少有关，而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液运送到脑组织深层活动的神经元所需的地方方面发挥着关键作用。我们发现 AD 中星形胶质细胞的关键葡萄糖转运分子存在缺陷的证据，以及经过基因改造以重现 AD 某些方面的小鼠品系的缺陷，该小鼠品系过度产生 β-淀粉样肽 (Aβ)，表现出失调。这些影响与空间记忆测试中的不良表现有关，小鼠在没有肥胖、高血糖、食欲不振的情况下也表现出这些问题。体力活动的变化、胰腺异常或胰岛素抵抗，这些发现激发了这样一种假设：即使没有明显的 AD，老化大脑中 Aβ 的水平也会开始升高，从而扰乱星形胶质细胞将外周葡萄糖输送到神经元的能力。在需要的地方我们进一步提出，载脂蛋白 E 基因的遗传变异体 ApoE4 可能通过其对基因调控的影响而导致葡萄糖缺乏。 AD 小鼠模型中葡萄糖转运蛋白的状态和功能的研究首先，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，特别是 ApoE4 的作用。与互动最后，我们将利用校园内的药物发现资源，试图从药理学上扭转葡萄糖失调，这些研究测试了关于 AD 中能量利用的特定元素的新假设。因此，该项目可能为治疗干预提供创新策略。 关联 该项目的重点是阿尔茨海默病的危险因素（例如炎症和载脂蛋白 E4 涉及大脑葡萄糖输送下降）对大脑能量利用的影响。这项研究将帮助我们了解阿尔茨海默病的危险因素如何导致精神恶化。它可以识别可以开发成治疗剂的化合物。