Interrogating the ability of ambroxol to modulate microglia functions
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.