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
University of Gothenburg
Harvard Medical School
Chalmers, Life Sciences, Systems and Synthetic Biology
Leah C. Beauchamp
Harvard Medical School
Julia Vincentini
Harvard Medical School
Shuqi Li
Harvard Medical School
Danielle S. LeServe
Harvard Medical School
Christian Gauthier
Harvard Medical School
Juliana R. Lopes
Harvard Medical School
Thais G. Moreira
Harvard Medical School
Millicent N. Ekwudo
Harvard Medical School
Zhuoran Yin
Harvard Medical School
Patrick da Silva
Harvard Medical School
Rajesh K. Krishnan
Harvard Medical School
Oleg Butovsky
Harvard Medical School
Laura M. Cox
Harvard Medical School
Howard L. Weiner
Harvard Medical School
Nature Communications
2041-1723 (ISSN) 20411723 (eISSN)
Vol. 15 1 3872Subject Categories
Neurosciences
Cell and Molecular Biology
DOI
10.1038/s41467-024-47683-w
PubMed
38719797