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.
Gut microbiota–driven brain Aβ amyloidosis in mice requires microglia
Disclosures: R.E. Tanzi reported "other" from MarvelBiome during the conduct of the study; and “other” from Amylyx, React Neuro, Cognitive Clarity, SiteRx, DRADS Capital, Neurogenetic Pharmaceuticals, Verge, Cognoptix, Genomind, Advantage, Jefferson Pharmaceuticals, Annovis, and Interaxon and personal fees from AZTherapies, Chromadex, Promis, Cerevance, FujiFilm, Sarepta, CAMP4, Neurona, Dolby Foundation, Cure Alzheimer's Fund, Boston U, and Takeda outside the submitted work. J.A. Gilbert reported “other” from BiomeSense Inc. and Holobiome Inc. outside the submitted work. No other disclosures were reported.
- Award Id(s): A2019032F
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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; Gut microbiota–driven brain Aβ amyloidosis in mice requires microglia. J Exp Med 3 January 2022; 219 (1): e20200895. doi: https://doi.org/10.1084/jem.20200895
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