Gut microbiota-driven brain Aβ amyloidosis in mice requires microglia

Hemraj B. Dodiya, Holly L. Lutz, Ian Q. Weigle, Priyam Patel, Julia Michalkiewicz, Carlos J. Roman-Santiago, Can Martin Zhang, Yingxia Liang, Abhinav Srinath, Xulun Zhang, Jessica Xia, Monica Olszewski, Xiaoqiong Zhang, Matthew John Schipma, Eugene B. Chang, Rudolph E. Tanzi, Jack A. Gilbert, Sangram S. Sisodia*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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, plaquelocalized 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.

Original languageEnglish (US)
Article numbere20200895
JournalJournal of Experimental Medicine
Volume219
Issue number1
DOIs
StatePublished - Dec 2 2021

ASJC Scopus subject areas

  • Medicine(all)

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