The Role of Microbial Immune Responses in Alzheimer's Disease

Myles Minter, PhD The University of Chicago


Sangram Sisodia, PhD The University of Chicago


Note: This grant ended early when the Dr. Minter moved to an industry position.

Alzheimer’s disease (AD) features brain deposition of amyloid-beta (Aβ) plaques and inflammation leading to dementia. Emerging evidence suggests that gut microbes (e.g. bacteria) can regulate the human immune system and influence brain function. This project will assess the role of gut microbes in regulating inflammation and Aβ deposition in mouse models of AD. Knowledge gained will advance our understanding of AD pathogenesis, how gut microbes communicate with the brain and potentially identify novel therapeutic targets.

Project Details

My research project, in conjunction with Prof. Sangram S. Sisodia, focuses on investigating the role of gut microbes in regulating the deposition of neurotoxic amyloid-beta (Aβ) protein and brain inflammation in Alzheimer’s disease (AD).

In the laboratory, I work with transgenic mice that recapitulate the Aβ deposition and inflammation observed in the devastating human disorder. Evidence now suggests that the microbes colonizing the host are critically important for brain function and inflammatory responses of the host. Microglia are a key brain-residing cell type that contribute to brain inflammation and are responsible for the clearance of neurotoxic Aβ. In the initial part of this project, I am investigating how depletion of the host microbiota influences their activity and ability to remove neurotoxic Aβ from the brain.

The complex diversity of the microbial communities living within us, and the myriad of metabolites they release (collectively termed the microbiome) contribute to multiple facets of your overall wellbeing. In line with the second aim of my project, I am now using complex metagenomic and metatranscriptomic analysis to identify specific gut-residing microbial species and metabolites that regulate host inflammation and Aβ deposition responsible for the progression of AD. This will be crucial in identifying what microbes are beneficial or harmful in the context of disease.

To further understand the precise mechanisms by which the host microbiome regulates inflammation and Aβ deposition in Alzheimer’s disease, I am colonizing transgenic AD mice that possess no microbiome with specific microbial strains and metabolites identified from my genomic analysis mentioned above. This final project aim is critical for elucidating the mechanisms by which microbes regulate brain inflammation and Aβ deposition in AD, but also to potentially identify novel microbially-derived therapeutics for the treatment of this devastating disorder.

Whereas the majority of preclinical AD research has been focused solely on the brain, my project involves a novel investigation into how microbial populations that reside within the gastrointestinal tract regulate host immunity and influence brain pathology. The microbiome field, specifically in the area of gut-brain axis communication, is rapidly evolving and has exciting implications for our understanding of AD and much needed therapeutic development that is outside the narrow scope of all current and previous therapeutic candidates investigated in drug trials. 

Findings from my research project will undoubtedly broaden our understanding of AD onset and progression by identifying mechanisms with which the host microbiome regulates disease pathology. Considering that our microbiomes are constantly changing in response to environmental factors such as diet, exercise, brain activity, sleep patterns, and pollutant exposure, these findings may provide insight into how to manage a microbiome profile for healthy aging and AD prevention. Most exciting of all is the possibility of identifying novel microbially-derived compounds that can be harnessed to treat the devastating effects of the disease in synergy with our current therapeutic options.