Author ORCID Identifier
https://orcid.org/0000-0003-3927-8862
Date of Graduation
8-2025
Document Type
Thesis (MS)
Program Affiliation
Biomedical Sciences
Degree Name
Masters of Science (MS)
Advisor/Committee Chair
Bhanu Priya Ganesh, PhD
Committee Member
Joo Eun Jung, PhD
Committee Member
Fudong Liu, PhD
Committee Member
Andrea Stavoe, PhD
Committee Member
Jennifer Walker, PhD
Abstract
Introduction: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β plaque accumulation, neuroinflammation, and cognitive decline. Recent evidence suggests that systemic factors, particularly the gut microbiota and its metabolites, play a significant role in shaping brain immune responses, including microglial activation. However, the mechanisms linking gut dysbiosis to microglial dysfunction in AD are poorly understood. The aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor responsive to tryptophan metabolites, has recently gained attention as a key regulator of neuroinflammation and microglial function. I hypothesize that the loss of beneficial microbial AHR ligands, specifically indole derivatives, during aging and AD progression contributes to a pro-inflammatory microglial state and accelerates AD progression.
Methods: The Tg2576 mouse model was used for this study, in which mice develop amyloid plaques and cognitive deficits at 12 months of age. Mice were aged to 9 and 15 months to study the progression of AD from the pre-symptomatic and post-symptomatic time points. Cognitive decline was assessed by Y-maze and novel object recognition test. Mass spectrometry metabolomics of blood plasma measured alterations in tryptophan pathways. Microglial AHR and inflammatory cytokine expression were characterized by flow cytometry. Additionally, human HMC3 microglial cells were treated with indole metabolites and lipopolysaccharide (LPS) to assess inflammatory responses in vitro.
Results: I assessed behavior, metabolite profiles, and microglial phenotypes across pre-symptomatic (9-month) and post-symptomatic (15-month) time points. Behavioral testing confirmed cognitive impairment in aged Tg2576+ mice. Plasma from aged symptomatic AD mice showed significantly reduced levels of beneficial microbial indole metabolites (e.g. 3-indole acetic acid, indoxyl-3-sulfate) and increased kynurenine. Microglial AHR and IL-1β expression was significantly upregulated in symptomatic AD mice compared to aged-matched controls and pre-symptomatic mice. In vitro, treatment of HMC3 microglial cells with indole metabolites suppressed LPS-induced pro-inflammatory cytokines IL-1β and IL-6, though AHR mRNA expression remained suppressed in inflammatory conditions. I also found that microglial AHR expression varies with age and microbiome exposure, with the lowest levels observed in pups and germ-free mice, and highest in aged wild-type mice, underscoring the importance of physiological context when analyzing AHR signaling.
Conclusion: My findings demonstrate that AHR expression in microglia is altered by age, disease state, and microbial metabolite availability. Loss of beneficial indole-derived AHR ligands and increased kynurenine levels in AD may shift AHR signaling toward a pro-inflammatory state, contributing to microglial dysfunction. These results highlight the importance of microbiota-derived metabolites in modulating neuroinflammation and identify AHR as a potential therapeutic target for restoring immune homeostasis in the aging and AD brain.
Recommended Citation
Alrousan, Ghalya E., "Microbial Metabolite Regulation of Microglial AHR Signaling in Alzheimer’s Disease" (2025). Dissertations & Theses (Open Access). 1477.
https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1477
Keywords
Alzheimer's disease, microglia, neuroinflammation, gut-brain axis, aryl hydrocarbon receptor, tryptophan metabolism, indole metabolites, kynurenine pathway, Tg2576 mouse model
Included in
Animal Experimentation and Research Commons, Disease Modeling Commons, Microbiology Commons, Nervous System Diseases Commons, Neurology Commons, Neuroscience and Neurobiology Commons