Bacteroidota inhibit microglia clearance of amyloid-beta and promote plaque deposition in Alzheimer’s disease mouse models
Journal article, 2024
The gut microbiota and microglia play critical roles in Alzheimer’s disease (AD), and elevated Bacteroides is correlated with cerebrospinal fluid amyloid-β (Aβ) and tau levels in AD. We hypothesize that Bacteroides contributes to AD by modulating microglia. Here we show that administering Bacteroides fragilis to APP/PS1-21 mice increases Aβ plaques in females, modulates cortical amyloid processing gene expression, and down regulates phagocytosis and protein degradation microglial gene expression. We further show that administering Bacteroides fragilis to aged wild-type male and female mice suppresses microglial uptake of Aβ1-42 injected into the hippocampus. Depleting murine Bacteroidota with metronidazole decreases amyloid load in aged 5xFAD mice, and activates microglial pathways related to phagocytosis, cytokine signaling, and lysosomal degradation. Taken together, our study demonstrates that members of the Bacteroidota phylum contribute to AD pathogenesis by suppressing microglia phagocytic function, which leads to impaired Aβ clearance and accumulation of amyloid plaques.
Author
Caroline Wasén
Harvard University
Chalmers, Life Sciences, Systems and Synthetic Biology
University of Gothenburg
Leah C. Beauchamp
Harvard University
Julia Vincentini
Harvard University
Shuqi Li
Harvard University
Danielle S. LeServe
Harvard University
Christian Gauthier
Harvard University
Juliana R. Lopes
Harvard University
Thais G. Moreira
Harvard University
Millicent N. Ekwudo
Harvard University
Zhuoran Yin
Harvard University
Patrick da Silva
Harvard University
Rajesh K. Krishnan
Harvard University
Oleg Butovsky
Harvard University
Laura M. Cox
Harvard University
Howard L. Weiner
Harvard University
Nature Communications
2041-1723 (ISSN) 20411723 (eISSN)
Vol. 15 1 3872Subject Categories (SSIF 2011)
Neurosciences
Cell and Molecular Biology
DOI
10.1038/s41467-024-47683-w
PubMed
38719797