Dr. Sisodia’s pioneering work has established a clear link between the gut microbiome and Alzheimer’s disease pathologies. Disrupting the gut microbiome with antibiotics in young mice prevents or reduces amyloid plaque formation and decreases neuroinflammation. Dr. Sisodia’s team also found that when they reduced the number of microglia in the brains of these mice, antibiotic treatment no longer lowered amyloid levels. Dr. Sisodia is interested in understanding how long it takes for changes in the gut microbiome to affect microglia activity and amyloid plaque levels.
In the previous funding cycle, the research team generated a mouse model with amyloid expression levels corrected to confirm that their findings in traditional amyloid models were not affected by the high amyloid expression in those models. Using these mice, they carefully tracked the early changes that occurred after antibiotic treatment and found a major shift in microglial gene expression. They also discovered that estradiol, a form of estrogen, plays a key role in how gut bacteria influence amyloid buildup. To test whether reducing estrogen could be protective, they removed the ovaries of female amyloid mice and demonstrated a dramatic reduction in both amyloid pathology and brain inflammation.
For this cycle, Dr. Sisodia’s team will expand this line of work. Firstly, they intend to map microglial gene expression changes in mouse brains to determine whether specific brain regions or the presence of amyloid pathology directly influence microglial gene expression. This will provide insights into the changes in microglia near amyloid pathology or in other key cell types. They will also conduct additional studies on the impact of removing ovaries in amyloid mouse models by assessing which genes change expression, thereby allowing them to identify pathways contributing to reduced pathology and inflammation. Finally, they will expand their study to also include the role of testosterone. Their preliminary work showed that removing testosterone resulted in worse amyloid pathology after antibiotic treatment, suggesting testosterone may have a separate beneficial mechanism, which they will explore.
