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 大脑组织中更深层的神经元活动单位。我们发现了关键的葡萄糖运输缺陷的证据 阿尔茨海默病中的星形胶质细胞分子，并在一种小鼠系中进行基因改造，以复制AD的某些方面。这 过度产生β-淀粉样多肽(A-β)的小鼠品系表现出循环血糖调节失调以及 大脑葡萄糖使用量的下降。这些影响与空间记忆测试中的糟糕表现有关。 进一步模仿人类阿尔茨海默病，小鼠在没有肥胖、高血糖、 食欲障碍、体力活动改变、胰腺异常或胰岛素抵抗。一起， 这些发现启发了一种假设，即Aβ的水平在老化的大脑中开始上升，即使在没有 Frank AD，扰乱了星形胶质细胞将外周葡萄糖带到神经元的能力，在神经元中，它是 与记忆和其他功能相关的神经活动增加。这一想法将通过 葡萄糖转运蛋白在衰老小鼠和人脑中的地位和功能的研究 正常衰老、AD和T2D的比较。通过对小鼠进行基因改造，我们将调节 最重要的星形细胞葡萄糖转运蛋白的水平，以确定它是否足以 中断的葡萄糖输送和记忆缺陷，以及ii)这些问题在 一个AD模型。因此，这些研究探索了一种关于能源利用的特定要素的新假设 老化的大脑及其与年龄相关的认知障碍的联系。因此，该项目可以提供 治疗干预的创新策略。

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 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.