Year: 2024
Type: article
Abstract: BACKGROUND: The gut microbiota and microglia play critical roles in Alzheimer's disease (AD), and more information is needed on how specific bacteria affect brain immunity in AD. We found that Bacteroides increased in aging Tg2576 mice and correlated with amyloid-beta (Aβ) plaques and hypothesized that Bacteroides worsens AD pathology by modulating microglia. Bacteroides is also elevated in AD patients and correlates with cerebrospinal fluid levels of Aβ and tau. METHOD: To test the effect of B. fragilis on Aβ plaques and microglia, we administered Bacteroides fragilis to APP/PS1-21 mice, assessed plaques by immunohistochemistry, and investigated microglial transcriptional responses on FAC sorted microglia by RNAseq. To determine whether B. fragilis suppressed microglial uptake, we also administered B. fragilis to aged WT mice for two months, then injected fluorescently labeled human Aβ1-42 peptides to the brain and measured FITC-Aβ by flow cytometry. RESULT: We found that B. fragilis increased Aβ plaques in female mice, modulated cortical gene expression involved in amyloid processing, and down regulated expression of microglial genes involved in phagocytosis and protein degradation. To investigate microglial phagocytic function, we administered B. fragilis to aged WT female and male mice for 2 months, injected fluorescently labeled human Aβ1-42 peptides to the brain, and found that B. fragilis suppressed uptake of Aβ in both male and female mice. Depleting murine Bacteroidota with metronidazole decreased amyloid load in aged 5xFAD mice, and activated microglial pathways related to phagocytosis, cytokine signaling, and lysosomal degradation. CONCLUSION: Taken together, these data suggest that bacteria in the Bacteroidota phylum contribute to AD pathogenesis by suppressing microglia phagocytic function, leading to impaired Aβ clearance and accumulation of plaques.
Source: Alzheimer s & Dementia
DOI: 10.1002/alz.087775
Author: Laura M Cox
Institutions: Brigham and Women's Hospital, Harvard University
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,000
OpenAlex ID: W4406051262