Administrative Supplement: Roles for Glucosensors in Taste Function

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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.