Microbiome Influences Microglia Phenotypes and Aβ Amyloidosis in a Sex-Specific Manner

Alzheimer’s disease (AD) features brain deposition of amyloid-β protein, forming plaques, and inflammation leading to dementia. Emerging evidence suggests that men and women exhibit different gut microbiota which regulates the human immune system and influences their brain function. Series of experiments will assess the role of gender-specific microbes in regulating inflammation and amyloid-β deposition using mouse models of AD. Knowledge gained will advance our understanding of AD susceptibility in men and women linking how different gut microbes educates immune system affecting disease course, and identify novel potential therapeutic options to treat AD in men and women separately.

Proposed series of studies focus on investigating the microbiota-brain axis in Alzheimer’s pathogenesis using transgenic mouse models of Alzheimer’s disease. I plan to investigate the cellular and molecular mechanism(s) by which the gut microbiome modulates brain immune function and amyloid-β pathology. Our previous reports demonstrate that the gut microbiome plays a vital role in Alzheimer’s amyloid pathology and microglial function in a sex-specific manner. As a follow-up, aim 1 of my current proposal will investigate if antibiotic-treated female mice can confer the reduced amyloid pathology and altered microglia characteristics after fecal transfer from antibiotic-treated male mice. The second aim will examine if an altered microglial function due to changes in the gut microbiome is causing reduced amyloid pathology in male mice and no changes in female mice. The last aim focuses to investigate if Alzheimer’s patients’ microbiome is pathogenic compared to control subjects. The idea that sex-specific microbiome could be a driving factor for different susceptibilities in men and women is an innovative approach. Results from these series of studies will strengthen the role of the microbiota-brain axis in Alzheimer’s disease and can shed light on the sexual dimorphism of Alzheimer’s disease. Data generated from these studies will open doors for future therapeutic intervention studies aiming at the microbiota-brain axis in Alzheimer’s and other neurodegenerative conditions.