Gut microbiota-driven brain Aβ amyloidosis in mice requires microglia

J Exp Med. 2022 Jan 3;219(1):e20200895. doi: 10.1084/jem.20200895. Epub 2021 Dec 2.

Abstract

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. 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. More importantly, fecal microbiota transplantation (FMT) from transgenic (Tg) or WT male donors into ABX-treated male mice completely restored Aβ amyloidosis, plaque-localized microglia morphologies, and Aβ-associated degenerative changes. Transcriptomic studies revealed significant differences between vehicle versus ABX-treated male mice and FMT from Tg mice into ABX-treated mice largely restored the transcriptome profiles to that of the Tg donor animals. Finally, colony-stimulating factor 1 receptor (CSF1R) inhibitor-mediated depletion of microglia in ABX-treated male mice failed to reduce cerebral Aβ amyloidosis. Thus, microglia play a critical role in driving gut microbiome-mediated alterations of cerebral Aβ deposition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / metabolism*
  • Amyloidosis / genetics
  • Amyloidosis / metabolism*
  • Animals
  • Antibodies / administration & dosage
  • Brain / drug effects
  • Brain / metabolism*
  • Chemokines / blood
  • Chemokines / genetics
  • Chemokines / metabolism
  • Cytokines / blood
  • Cytokines / genetics
  • Cytokines / metabolism
  • Fecal Microbiota Transplantation
  • Feces / microbiology
  • Female
  • Gastrointestinal Microbiome / drug effects
  • Gastrointestinal Microbiome / genetics
  • Gastrointestinal Microbiome / physiology*
  • Gene Expression Profiling / methods
  • Gene Ontology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microglia / metabolism*
  • RNA-Seq / methods
  • Sex Factors

Substances

  • Amyloid beta-Peptides
  • Antibodies
  • Chemokines
  • Cytokines