Researchers from the University of Chicago have discovered that microglia play a key role in the relationship between the gut microbiome and β-amyloid deposits in male mice in a model of Alzheimer’s disease (AD).

Their findings are published in the Journal of Experimental Medicine, in a paper titled, “Gut microbiota–driven brain Aβ amyloidosis in mice requires microglia.”

“We previously demonstrated that lifelong antibiotic (ABX) perturbations of the gut microbiome in male APPPS1-21 mice lead to reductions in amyloid β (Aβ) plaque pathology and altered phenotypes of plaque-associated microglia,” the researchers wrote. “Here, we show that a short, 7-d treatment of preweaned male mice with high-dose ABX is associated with reductions of Aβ amyloidosis, plaque-localized microglia morphologies, and Aβ-associated degenerative changes at 9 wk of age in male mice only.”

“Our past work has shown that if you give mice antibiotics beginning shortly after birth, you see a reduction of amyloid deposition specifically in male animals from this particular model of Alzheimer’s disease,” explained senior author Sangram Sisodia, PhD, the Thomas A. Reynolds Sr. family professor of neurobiology. “In parallel, in the past, we’ve looked at the biology of microglia in the brain and find that in male animals, there are significant changes in the gene expression and morphologies of the cells. In this study, we decided to look at the microglia specifically in the context of this paradigm.”

The researchers used APPPS1-21 mice, a popular genetic model of AD. These animals develop pathologies associated with AD, including the amyloid plaques thought to play a central role in the neurodegenerative condition. The researchers observed a reduction in the levels of β-amyloid in the male brain at nine weeks of age. Female mice, however, showed no such differences.

The research team, led by Hemraj Dodiya, PhD, a postdoctoral fellow in the Sisodia lab, determined that the reduction in amyloid plaques was linked to the changes in the gut microbiome by conducting daily fecal matter transplants (FMT) on male mice that had been treated with antibiotics.

“Microglia have a memory,” explained Sisodia. “We don’t know exactly what this memory is, but we know that they can respond to a pathogen or perturbation by changing their shape and gene expression and they can sustain those changes for a long time. What we’re seeing in this study is that after antibiotic treatment early in life, amyloid deposition is significantly reduced in males and not in females. And we see that the microglial transcriptome—their gene expression—is changed as well. But if you feed bacteria present in the feces from another untreated mouse to antibiotic-treated mice, you restore the pathology, as well as the microglial phenotype. The final question is, are the microglia responsible for the amyloidosis, and if so, how are the microglia doing this?”

“Really, this study shows us three key things,” said first author Dodiya. “The first is that we see these sex-specific changes in amyloidosis in the brain after early life perturbations in the gut microbiome. The second is that simply conducting a fecal matter transplant is enough to restore the amyloidosis after antibiotic treatment, and the third is that the microglia are an essential factor driving the microbiome-initiated changes.”

The research team is conducting further studies that more directly target microglia to ensure the effects of PLX5622, a drug called PLX562—which kills microglia in the mouse brain, as well as some peripheral immune cells in the blood stream—on innate immune cells throughout the body are not affecting amyloidosis in the brain. They hope to clarify what signals the gut is sending to the brain that lead to these changes in the microglia, and how that, in turn, leads to changes in the amyloid plaques.

The team also is exploring the question of why these effects are only seen in male mice. “It’s an astounding effect,” said Sisodia. “In females, the microglia don’t seem to be affected at all by perturbations in the microbiome. Research in the past has shown that microglia from male and female animals are very different during development and during aging, but what are the contributing factors? It’s likely to be an effect of sex hormones, but then what are the effects on the microbiome?”

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