Date of Award

January 2023

Document Type

Thesis

Degree Name

Master of Public Health (MPH)

Department

School of Public Health

First Advisor

Vasilis Vasiliou

Abstract

Metformin, a first-line therapy for Type 2 Diabetes Mellitus (T2DM), has been shown to have numerous health benefits in neurodegenerative disease progressions, including Alzheimer’s disease (AD). Vasiliou et al. have recently proposed that metformin is able to scavenge endogenously produced aldehydes such as 4-hydroxy-2-nonenal (4-HNE), which are thought to contribute to the progression and development of AD. Preliminary in vitro and in silico studies demonstrate that metformin scavenges 4-HNE leading to adduct formation. Therefore, this study sought to determine if metformin adducts 4-HNE in a living system. We hypothesize that metformin can scavenge 4-HNE in HEK 293T cells and will lead to a recovery in cell viability lost due to 4-HNE-induced damage.HEK 293T cells were treated at different concentrations of metformin using two treatment methods: 1. Metformin and 4-HNE co-treatment for 12 hours, 2. Metformin pre-treatment for 12 hours followed by 4-HNE treatment for 12 hours. Changes in cell viability were assessed using the MTT and CellTiter 96® AQueous One Solution Cell Proliferation Assays, as compared to the no-treatment and positive controls. Ultimately, no significant recovery in cell viability was observed in either treatment method at lower concentrations of metformin (0.1, 1 and 5 mM). However, higher concentrations of metformin (10 and 20 mM) significantly recovered cell viability lost due to 4-HNE toxicity. In the co-treatment method, cell viability recovery was 36.76% (p<0.05, 10 mM metformin) and 30.95% (p<0.05, 20 mM metformin) when compared with the group only treated with 4-HNE. In the pre-treatment method, cell viability recovery was 12.44% (p<0.05, 10 mM metformin) and 10.47% (p<0.05, 20 mM metformin) when compared with the group treated only with 4-HNE. Ultimately, this study shows that metformin at high concentrations can recover cell viability lost due to 4-HNE-induced damage in HEK 293T cells, which highlights a potential area of exploration for future Alzheimer’s disease research.

Comments

This thesis is restricted to Yale network users only. It will be made publicly available on 05/10/2025

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