Administrative Supplement: Roles for Glucosensors in Taste Function

项目总结 高糖饮食是肥胖、糖尿病和神经退行性疾病的重要风险因素， 如阿尔茨海默氏症。这些物质所谓可口的“甜味”在 提高他们的吸引力，有时是以牺牲均衡的饮食为代价的。在人类中，阿尔茨海默病进展的标志是 对甜味的敏感度降低，对更甜的食物和液体的渴望增加。而当 人们通常认为这些味觉缺陷是由于中枢神经系统功能受损造成的，外周 与AD最终发作相关的条件也可能影响其外周末端器官的味觉处理， 味蕾。事实上，关于味觉异常是如何发展的，包括它们是否出现，人们知之甚少。 早期并有助于AD的进展。亲本R01的一个目的是研究葡糖激酶，一种 我们发现在小鼠味觉细胞中表达的葡萄糖感受器中介有助于 糖。到目前为止，我们发现味觉葡糖激酶受代谢状态和饮食糖的调节，并且 有助于检测口腔中含葡萄糖的糖类。尽管这些进程不会 需要典型的甜味受体(T1R2+T1R3)，初步数据包含在本行政补充资料中 现在发现葡萄糖激酶活性会影响小鼠体内甜味受体的表达。此外，在一组试点中， 研究，包括这里，我们发现在转基因AD小鼠模型中味蕾发生了显著的变化， 即使是在年轻的成年时期。3xTg鼠标的味蕾要小得多，味蕾显示出高水平的 炎性细胞因子、肿瘤坏死因子α和较少的葡萄糖激酶，尽管还需要进一步的测试。准确地说，这些 无论它们是否与伴随的甜味受体有关，都会出现形态和分子上的异常 损失，以及它们最终是如何影响口味偏好的，目前尚不清楚。因此，这一行政管理的目标是 补充是扩展亲本R01的目标1以研究味蕾随年龄的变化 家族性和散发性阿尔茨海默病的微环境和味觉引导行为。为此，我们将使用 免疫组织化学技术和严格的行为味觉测试研究两种常见的转基因小鼠 品系，3xTg和APOE4敲入，它们在成年期对AD的遗传易感性不同。这个 这些目标的结果将使我们更好地了解味觉葡萄糖感受器如何在 寿命和对与阿尔茨海默病相关的潜在代谢炎症条件的反应。这 对于制定新的策略来评估AD症状和遏制过量糖来说，知识将是重要的 摄入量加剧了疾病的发展。

PROJECT SUMMARY Diets high in sugar are significant risk factors for obesity, diabetes, and neurodegenerative diseases, such as Alzheimer’s. The so called palatable “sweet” taste of these substances play a significant role in promoting their appeal, sometimes at the expense of a balanced diet. In humans, AD progression is marked by a decreased sensitivity to sweet taste, and increased cravings for more intensely sweet foods and fluids. While it is commonly assumed these taste deficits result from impaired central nervous system function, the peripheral conditions associated with the eventual onset of AD may also affect taste processing at its peripheral end organ, the taste bud. In fact, very little is known about how the gustatory abnormalities develop, including if they emerge early and contribute to AD progression. One aim of the parent R01 is to investigate how glucokinase, a glucosensor intermediary, we found to be expressed in murine taste cells, contributes to the hedonic appeal of sugar. To date, we showed that gustatory glucokinase is regulated by metabolic state and dietary sugar, and contributes to the ability to detect glucose-containing sugars in the oral cavity. Although these processes do not require the canonical sweet receptor (T1R2+T1R3), preliminary data included in this administrative supplement now show that glucokinase activity affects sweet receptor expression in mice. Furthermore, in a set of pilot studies, included here, we discovered significant alterations to the taste buds in a transgenic AD mouse model, even in young adulthood. The 3xTg mouse has significantly smaller taste buds, which display high levels of the inflammatory cytokine, TNFα, and less glucokinase, though further testing is needed. Precisely when these morphological and molecular aberrations emerge, whether they are associated with concomitant sweet receptor loss, and how they ultimately affect taste preferences remain unknown. Thus, the goal of this administrative supplement is to extend Aim 1 of the parent R01 to investigate age-dependent changes in the taste bud microenvironment and taste-guided behaviors in familial and sporadic AD. To do this, we will use immunohistochemical techniques and rigorous behavioral taste testing to study two common transgenic mouse lines, 3xTg and APOE4 knock in, which vary in their genetic predisposition to AD, across adulthood. The outcomes of these aims will provide a better understanding of how gustatory glucosensing changes across the lifespan and in response to the underlying metabolic-inflammatory conditions associated with AD. This knowledge will be important for developing new strategies to assess AD symptoms and curb the excess sugar intake exacerbating disease progression.