Thesis Format
Monograph
Degree
Master of Science
Program
Anatomy and Cell Biology
Supervisor
Whitehead, Shawn N.
2nd Supervisor
Pasternak, Stephen
Affiliation
Robarts Research Institute
Co-Supervisor
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by progressive cognitive decline and pathologically by the accumulation of amyloid-beta plaques and neurofibrillary tangles in the brain. Additionally, dysregulation of microglia phagocytosis, lysosomal activity, and inflammatory response has been extensively implicated in the pathogenesis of AD. Work in this thesis aimed to assess the impact of ambroxol on microglial function, both in vitro and in vivo. Ambroxol, recognized for its therapeutic promise in neurodegenerative diseases through the facilitation of transcription factor EB (TFEB) protein translocation to neuronal nuclei, was investigated for its effects on microglia. Our findings demonstrated that exposure to ambroxol induced TFEB protein nuclear localization in both resting and microglia activated to a pro-inflammatory phenotype, accompanied by an upregulation in transcripts encoding lysosomal enzymes. Furthermore, microglia activation prior to ambroxol treatment resulted in a partial prevention of inflammatory responses observed by a reduction in TNFα transcripts. In vivo experiments conducted in 3x Tg mice revealed elevated numbers of microglia in the hypothalamus coupled with reduced microglial activation following two months of ambroxol diet. Overall, our study provides evidence supporting the potential therapeutic utility of ambroxol in increasing functions in activated microglia and reducing microglia activation.
Summary for Lay Audience
Alzheimer's disease (AD) is a condition where the brain's ability to think and remember declines over time. This happens because harmful substances like amyloid-beta plaques and Tau neurofibrillary tangles build up in the brain. Normally, microglia, which are like the brain's garbage collectors, help remove these harmful substances. But in Alzheimer's, microglia become less effective at cleaning up and start releasing chemicals that cause inflammation. In this study, we looked at a drug called ambroxol to see if it could help microglia work better. Ambroxol has been suggested as a treatment for other brain diseases like Parkinson's. The researchers found that ambroxol boosts the activity of a protein called transcription factor EB (TFEB), which helps increase transcription of genes that are involved in clearance mechanisms within the cell. We hypothesized that ambroxol exposure to microglia would help increase their ability to clear toxic proteins from the brain. This study found that ambroxol not only increased TFEB activity but also reduced the release of inflammatory signals from microglia. In experiments with cells and mice that have Alzheimer's-like symptoms known as triple transgenic (3x Tg) mice, ambroxol reduced the activation of microglia. These results suggest that ambroxol could be a promising treatment for Alzheimer's by helping microglia clear away harmful substances in the brain.
Recommended Citation
Gajavelli, Sairam, "Interrogating the ability of ambroxol to modulate microglia functions" (2024). Electronic Thesis and Dissertation Repository. 10120.
https://ir.lib.uwo.ca/etd/10120
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