Sex-specific effects of microbiome perturbations on cerebral Aβ amyloidosis and microglia phenotypes

Area of Science:

• Neuroscience
• Microbiology
• Immunology

Background:

• Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaques and neuroinflammation.
• The gut microbiome's influence on brain health and AD pathogenesis is increasingly recognized.
• Sex-specific differences in AD progression and response to interventions are well-documented.

Purpose of the Study:

• To investigate the generality of the gut microbiome's effect on Aβ pathology across different mouse models.
• To determine the sex-specific impact of antibiotic-induced gut dysbiosis on Aβ pathology and microglial responses.
• To establish a causal link between the gut microbiome and Aβ amyloidosis through fecal microbiota transplantation.

Main Methods:

• Treatment of APPPS1-21 mice with an antibiotic cocktail (ABX) to perturb the gut microbiome.
• Assessment of Aβ plaque load, microglial morphology, and gene expression in male and female mouse brains.
• Fecal microbiota transplantation (FMT) from male APPPS1-21 donors to ABX-treated male APPPS1-21 recipients.

Main Results:

• ABX treatment reduced Aβ pathology and altered microglial morphology in male APPPS1-21 mice, but not in females.
• ABX altered microglial homeostatic gene expression in males, but not females.
• FMT partially restored the gut microbiome, Aβ pathology, and microglial morphology in ABX-treated male mice.

Conclusions:

• A perturbed gut microbiome causally modulates Aβ amyloidosis and microglial physiology in a sex-specific manner in mouse models.
• The gut microbiome represents a potential therapeutic target for Alzheimer's disease.
• Sex differences are critical considerations in microbiome-based interventions for neurodegenerative diseases.