Compromised function of a glial glucose transporter in aging and Alzheimer's disease

衰老和阿尔茨海默病中神经胶质葡萄糖转运蛋白的功能受损

• 批准号: 10542429
• 负责人: Steven W Barger
• 金额: $ 38万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10542429
• 关键词: Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Astrocytes; Attenuated; Biological Assay; Blood Circulation; Blood Vessels; Brain; Cell membrane; Cells; Cerebral cortex; Cerebrum; Chickens; Chronic; Circulation; Cognition; Cognitive; Compensation; Defect; Dependence; Desire for food; Deterioration; Diabetes Mellitus; Disease; Elderly; Elements; Endothelium; Energy Metabolism; Exhibits; GLUT-3 protein; Genetic; Glucose; Glucose Transporter; Glucose tolerance test; Hippocampus; Human; Hyperglycemia; Impairment; Insulin; Insulin Resistance; Interruption; Link; Memory; Memory Loss; Memory impairment; Modification; Mus; Nerve Degeneration; Nervous System Physiology; Neurologic; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overweight; Pancreas; Performance; Peripheral; Phenotype; Physical activity; Play; Process; Protein Isoforms; Proteins; Psyche structure; Resolution; Role; SLC2A1 gene; Specimen; Supporting Cell; Surveys; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Work; abeta accumulation; age effect; age related; aging brain; amyloid pathology; behavior test; blood glucose regulation; brain parenchyma; brain tissue; cell type; conditional knockout; egg; glucose metabolism; glucose tolerance; glucose transport; hyperphosphorylated tau; impaired glucose tolerance; innovation; metabolic rate; neurophysiology; normal aging; novel; overexpression; spatial memory; trafficking; trait; uptake

SUMMARY Aging is the most powerful risk factor for Alzheimer’s disease (AD), and it contributes to the odds of type-2 diabetes mellitus (T2D) as well. Aging is also 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. This idea will be tested through studies of the status and function of glucose transport proteins in aging mouse and human brains, along with comparisons between normal aging, AD, and T2D. Through genetic modification of mice, we will modulate the levels of the most important astrocytic glucose transporter to determine if it is i) sufficient to bring about interrupted glucose delivery and memory deficits, and ii) necessary for the presentation of these problems in an AD model. These studies thus explore a novel hypothesis about a specific element of energy utilization in the aging brain and its connection to age-related cognitive impairment. As such, the project may provide innovative strategies for therapeutic intervention.

概括 衰老是阿尔茨海默病 (AD) 最强大的危险因素，它会增加 2 型阿尔茨海默病的发病率 糖尿病（T2D）也与大脑消耗葡萄糖的减少有关。 星形胶质细胞在将葡萄糖从血液运送到需要的地方方面发挥着关键作用。 我们发现了大脑组织深处的神经元活动单位的关键葡萄糖转运存在缺陷的证据。 AD 和经过基因改造以重现 AD 某些方面的小鼠系中的星形胶质细胞分子。 过度产生 β-淀粉样肽 (Aβ) 的小鼠品系表现出循环葡萄糖失调，以及 大脑葡萄糖消耗的下降与空间记忆测试中的不良表现有关。 进一步模仿人类AD，小鼠在没有肥胖、高血糖、 食欲不振、体力活动改变、胰腺异常或胰岛素抵抗。 这些发现激发了这样的假设：即使没有，Aβ 的水平在衰老的大脑中也会开始上升。 坦率地说，AD 扰乱了星形胶质细胞将外周葡萄糖带到神经元的能力，而神经元是神经元所需要的 与记忆和其他功能相关的神经活动的增加将通过以下方式进行测试。 研究衰老小鼠和人类大脑中葡萄糖转运蛋白的状态和功能，以及 正常衰老、AD 和 T2D 之间的比较 通过对小鼠进行基因改造，我们将调节 最重要的星形胶质细胞葡萄糖转运蛋白的水平，以确定它是否 i) 足以实现 葡萄糖输送中断和记忆缺陷，以及 ii) 在以下情况中出现这些问题所必需的 因此，这些研究探索了关于能源利用的特定要素的新假设。 因此，该项目可能会提供衰老的大脑及其与年龄相关的认知障碍的联系。 治疗干预的创新策略。