Graduation Year
2024
Document Type
Master's Thesis
Degree
Master of Science
Program
Biological Science
Program Director
Meredith Protas, PhD
First Reader
Gordon Lithgow
Second Reader
Dipa Bhaumik
Abstract
Alzheimer's Disease (AD) is a neurodegenerative disease that commonly progresses with age resulting in loss of cognitive function. AD pathology is characterized by amyloid-beta (Aß) plaques and tau neurofibrillary tangles in the brain1.
Animal models of AD have allowed scientists to better understand the disease pathology and test potential therapeutics2. Caenorhabditis elegans (C. elegans), a tractable animal model, and mammalian cell culture models provide a way of rapidly screening compounds for effectiveness in delaying AD pathogenesis. In this study we specifically focused on the Aß pathogenesis of AD. Previously, a high throughput screen with a natural product library and using C. elegans AD model from our laboratory showed that two compounds kinetin (KT) and retrorsine (RTS), delayed Aß induced pathogenesis. In another study from our laboratory using a thermotolerance survival assay as a screening method, azure B (AzB) a metabolite of methylene blue (MB) was identified as a hit compound from the L5300 Mitochondria Target Activation Library (Targetmol). AzB also delayed Aß induced pathogenesis in the C. elegans AD models. In the present study, we performed a detailed investigation on KT, RTS, MB and Azure C (AzC), another metabolite of MB with focus on lifespan studies and Aß induced pathogenesis studies.
Our studies show that compound KT and RTS delay onset of pathogenesis caused by Aß expression in C. elegans muscle and neuronal models. In the C. elegans muscle model this delay in pathogenesis was not dependent on NRF2 (SKN-1 in C. elegans). KT extended lifespan in C. elegans when exposed to it during development. RTS did not extend lifespan in C. elegans. In cell culture models, KT but not RTS treatment reduced oxidative stress levels induced by Aß in microglia cells. KT also protected against glutamate-induced toxicity in mouse neuronal cells. AzC and MB also extended lifespan under particular conditions and delayed onset of Aß induced pathogenesis in the C. elegans AD muscle model. In cell culture models, AzC and MB treatment reduced oxidative stress levels induced by Aß and protected neuronal cells against glutamate-induced toxicity. Our work demonstrates that KT, RTS, AzC and MB have positive effects in AD models. Further work, would help us better understand whether these compounds could potentially be used as a therapeutic agent in AD.