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 Zhang, Yingxia Liang, Abhinav Srinath, Xulun Zhang, J. Xia, Monica Olszewski, Xiaoqiong Zhang, Matthew J. Schipma, Eugene B. Chang, Rudolph E. Tanzi, Jack A. Gilbert, Sangram S. Sisodia
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.