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: 10610184
• 负责人: Steven W Barger
• 金额: $ 6.92万
• 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/10610184
• 关键词: Acute; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Apolipoprotein E; Astrocytes; Back; Behavior; Biological Assay; Blood Circulation; Blood Vessels; Brain; Brain Diseases; Cell membrane; Cerebrovascular system; Cerebrum; Chronic; Cognitive; Cognitive deficits; Defect; Dementia; Disease; Drops; Eating; Elements; Endothelial Cells; Endothelium; Estradiol; Estrogen Replacements; Estrogens; Event; Exhibits; Female; Genes; Genetic; Genetic Engineering; Genetic Polymorphism; Genotype; Glucose; Glucose Transporter; Gonadal Steroid Hormones; Hematology; High Fat Diet; Hormone replacement therapy; Hormones; Hot flushes; Human; Hyperglycemia; Impaired cognition; Incidence; Individual; Investigation; Link; Measures; Membrane; Memory; Memory impairment; Menopause; Metabolic; Modality; Modeling; Mus; Nerve Degeneration; Neurologic Deficit; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Ovariectomy; Ovary; Peripheral; Phenotype; Play; Postmenopause; Protein Isoforms; Risk; Rodent; Role; SLC2A1 gene; Safe Sex; Sex Differences; Testing; Therapeutic Intervention; Transgenic Mice; Variant; Wild Type Mouse; Woman; abeta accumulation; age related; aging brain; apolipoprotein E-3; apolipoprotein E-4; blood glucose regulation; brain health; brain tissue; genetic risk factor; glucose metabolism; glucose tolerance; glucose transport; glycemic control; human female; innovation; male; men; mental function; metabolic rate; mouse model; novel; protective effect; resilience; sex; spatial memory; western diet

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 male mice of a line genetically modified to reproduce some aspects of AD. Though the females also overproducing the β-amyloid peptide (Aβ), only males exhibit dysregulation of circulating glucose, a decline in brain glucose usage, and spatial memory deficits. Human females have a higher incidence of AD, but this is manifest after menopause, which mice do not experience. This suggests that the female mice may be protected by sex-specific hormones such as estrogens. This supplement will test this hypothesis by examination of female Aꞵ-expressing mice that have had their ovaries removed, and the role of estrogen will be determined by adding this hormone back to some of the females. Peripheral glucose regulation, brain glucose usage, and memory behavior will be tested to determine if loss of estrogens puts the female mice at risk the same deficits seen in males. Because differences in the gene for apolipoprotein E (ApoE) affect the risk for AD in a sex-dependent way, we will also assay the parameters above in mice that have been genetically engineered to express two variants of human ApoE. These studies thus explore a novel hypothesis about a specific element of energy utilization as it pertains to the aging brain and its connection to sex-related risks. As such, the project may provide innovative strategies for therapeutic intervention.

总结 衰老是阿尔茨海默病（AD）最强大的风险因素，它有助于2型糖尿病的发病率。 糖尿病（T2 D）。衰老也与大脑对葡萄糖的使用减少有关，葡萄糖是大脑最重要的代谢物。 重要的燃料。星形胶质细胞在将葡萄糖从血流运送到需要它的地方方面起着关键作用。 脑组织深处的神经元活动单位。我们发现了一个关键的葡萄糖转运缺陷的证据 在AD和雄性小鼠中，星形胶质细胞的分子被遗传修饰以复制AD的某些方面。 虽然雌性也过度产生β-淀粉样肽（Aβ），但只有雄性表现出β-淀粉样肽（Aβ）的调节障碍。 循环葡萄糖、脑葡萄糖使用下降和空间记忆缺陷。人类女性 AD的发病率更高，但这在绝经后很明显，而小鼠不会经历。这表明 雌性小鼠可以受到性别特异性激素如雌激素的保护。本增刊将对此进行测试 通过检查切除卵巢的雌性A β表达小鼠的假设，以及 雌激素将通过将这种激素加回一些雌性来确定。外周葡萄糖 调节，大脑葡萄糖的使用和记忆行为将被测试，以确定是否雌激素的损失， 雌性小鼠的风险与雄性小鼠相同。因为载脂蛋白E基因的差异 （ApoE）以性别依赖性方式影响AD风险，我们还将在小鼠中测定上述参数， 已经被基因工程改造成表达两种人类ApoE变体。这些研究因此探索了一部小说 关于能量利用的特定元素的假设，因为它与衰老的大脑及其与 性相关风险。因此，该项目可能为治疗干预提供创新战略。