Graduation Year
2020
Document Type
Master's Thesis
Degree
Master of Science
Program
Biological Science
Program Director
Meredith Protas, PhD
First Reader
Pankaj Kapahi, PhD
Second Reader
Kegan Donlan, PhD
Abstract
Diabetes patients are at higher risk of contracting an age-related neurodegenerative disease such as Alzheimer’s disease (AD). However, the mechanisms which link these diseases are poorly understood. We hypothesize that glucose and elevated levels of the glycolysis by product advanced glycation end-products (AGEs), may be involved. AGEs accumulate with age and are elevated in both diabetic and AD patients. Diabetes is a metabolic disorder for which consumption of sugar-rich diets is a major risk factor and is central to etiology in the vast majority of cases.
We show that transgenic C. elegans expressing wild type (WT) human tau fed a diet supplemented with glucose drastically reduces lifespan, increases feeding behavior, reduced motility, and results in the accumulation of AGEs. Interestingly, C. elegans expressing A152T mutant human tau had improved lifespan and motility when given a high glucose diet, indicating this tau mutation interacts with metabolism in a drastically different manner. Tau expressing animals (WT and A152T) fed the AGE, methylglyoxal-derived methyl-glyoxal-hydroimidazolone (MGH1), have shortened lifespans, increased feeding, and reduced motility. Tau expression appears to have general impacts on overall gene expression, as human tau expressing worms (WT and A152T) exhibit disrupted fat metabolism and glyoxalase expression. Therefore, our data supports the hypothesis that glucose and AGEs may act as a mechanistic link between Alzheimer’s disease, other tauopathies, and diabetes, and that therapies aimed at inhibiting AGE formation may prove beneficial in treating these diseases.