The impact of high dietary glucose on amyloid-beta proteotoxicity in Caenorhabditis elegans
Date
2024
Authors
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Journal ISSN
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Publisher
University of Delaware
Abstract
Alzheimer’s disease (AD) is the leading neurodegenerative disorder worldwide, with an estimated 60 million individuals currently afflicted. Pathological features of this debilitating condition include amyloid-beta (Aβ) accumulation, bioenergetic defects, increased oxidative stress, and impaired glucose metabolism. Since there is currently no disease-modifying treatment for AD, it is essential to understand how modifiable risk factors such as diet impact disease onset and progression. It is difficult to determine the impact of specific nutrients in humans due to complex diet, organismal complexity, genetic diversity, and indirect effects of the gut microbiome. Individuals with abnormal blood sugar levels and glucose utilization are at greater risk for AD, likely because glucose is required to fuel neuronal function. Yet we lack an understanding of how the interplay between glucose and other macro/micronutrient availability impacts brain health. To investigate the effect of excess sugar on amyloid-beta proteotoxicity, I used a transgenic strain of C. elegans expressing the toxic human Aβ1-42 peptide in the body wall muscles, which produces AD-like pathogenic features such as a time-dependent paralysis that mimics progression of the disease, reduced ATP levels, and increased reactive oxygen species. We discovered that glucose supplementation accelerated paralysis in Aβ animals that consumed OP50 E. coli yet had no effect on worms fed HB101 E. coli. While vitamin B12 can protect against Aβ-induced proteotoxicity, B12 is not the factor in the HB101 diet that nullifies the toxic effects of excess glucose levels. To determine how this diet was protective we performed RNA-Seq and observed downregulation of the predicted facilitated glucose transporter F14E5.1 (fgt-2) in animals fed HB101. Loss of fgt-2 slowed Aβ-induced paralysis, alleviated bioenergetic defects, and reduced ROS accumulation in Aβ animals fed OP50. In the presence of excess glucose, the fgt-2(tm3206) mutation abrogated accelerated Aβ-induced paralysis, resulting in a similar time to paralysis regardless of the diet consumed. These findings suggest that fgt-2 impacts Aβ-induced proteotoxicity, potentially by modulating glucose metabolism via glucose transporter availability. However, fgt-2 is not the primary glucose transporter in C. elegans, and its function is not entirely known. In order to further investigate the significance of glycolytic transport in Aβ-induced proteotoxicity, I crossed the Aβ transgene with fgt-1, the primary glucose transporter. Loss of fgt-1 resulted in an accelerated time to paralysis, suggesting the importance of the role glucose import plays. Loss of both fgt-1 and fgt-2 produces a similar result to the fgt-1 single mutant, indicating that either the protective effects of fgt-2 rely on fgt-1 or the function of the primary glucose transporter is crucial regardless of protection elsewhere. Overall, my research highlights the importance of glycolytic transport for overall well-being while demonstrating the impact excess sugar intake has on disease pathologies.
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Keywords
Amyloid-beta accumulation, Alzheimer’s disease, Proteotoxicity, Glycolytic transport, Glucose transporter