Graduation Year
2022
Document Type
Master's Thesis
Degree
Master of Science
Program
Biological Science
Program Director
Meredith Protas, PhD
First Reader
Pankaj Kapahi, PhD
Second Reader
Kiyomi Kaneshiro, PhD
Abstract
In the aging brain, cells undergo stress, inflammation, loss of replicative ability and in some cases cell death. Hyperglycemic conditions have been shown to exacerbate these effects. Recent literature has begun to regard Alzheimer’s Disease as a “Type 3 Diabetes Mellitus,” implicating loss of insulin sensitivity and increased oxidative stress as contributing factors. Hyperglycemic conditions can overwhelm the cellular capacity to detoxify harmful glycolytic byproducts such as methylglyoxal (MGO). Intact MGO reacts readily with nearby proteins or lipids to form Advanced Glycation End products (AGEs), of which the accumulation over time has been linked to many age-associated pathologies. Our lab developed Gly-Low, designed to increase MGO detoxification and thus reduce AGEs and their associated conditions. We found that aged mice treated with Gly-Low showed improved lifespan, reduced food consumption, and mitigation of weight gain. This thesis explores the cellular mechanism by which these effects were occurring. We found that Gly-Low reduced the hippocampal amyloid burden of an AD mouse model and determined that this effect was unlikely due to a direct effect on astrocyte uptake of amyloid. Additionally, acute MGO exposure induced cytotoxic effects and chronic MGO exposure increased a key senescence marker in multiple cell lines, though Gly-Low’s ability to defend against the induced cytotoxicity and increased senescence marker was not conclusively determined. This work contributes to the foundation for future studies intended to elucidate the biochemical underpinnings of Gly-Low’s phenotypic effects.