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

摘要 衰老是阿尔茨海默病(AD)最强大的风险因素，它增加了患2型的几率 糖尿病(T2D)。衰老还与大脑对葡萄糖的使用减少有关，葡萄糖是大脑中最重要的 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起着关键作用 位于脑组织深处的神经元活动单位。我们发现了关键的葡萄糖运输缺陷的证据 阿尔茨海默病和雄性小鼠中的星形胶质细胞分子经过基因改造后复制了阿尔茨海默病的某些方面。 虽然雌性也过度产生β-淀粉样多肽(Aβ)，但只有雄性表现出调节失调。 循环中的葡萄糖，大脑葡萄糖使用量的下降，以及空间记忆缺陷。人类女性有一种 阿尔茨海默病的发病率更高，但这在绝经后表现得很明显，这是老鼠没有经历过的。这表明 雌性小鼠可能会受到雌激素等性别特异性激素的保护。本增刊将检验这一点 通过对卵巢摘除的表达ꞵ的雌性小鼠的检查提出假说，以及 雌激素将通过将这种荷尔蒙重新添加到一些雌性体内来确定。外周葡萄糖 将对调节、大脑葡萄糖使用和记忆行为进行测试，以确定雌激素的丢失是否会使 雌性小鼠面临着与雄性小鼠相同的缺陷风险。因为载脂蛋白E基因的差异 (APOE)以性别依赖的方式影响AD的风险，我们也将在 已经通过基因工程表达了两种不同的人类载脂蛋白E。这些研究因此探索了一部小说 关于能量利用的一个特定元素的假说，因为它与衰老的大脑有关，并与 与性有关的风险。因此，该项目可能为治疗干预提供创新的策略。

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.