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Gut microbiota-driven brain Aβ amyloidosis in mice requires microglia
Hemraj B Dodiya1, Holly L Lutz2, Ian Q Weigle1
1Department of Neurobiology, The University of Chicago, Chicago, IL.
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.
Insights
Gut microbiome alterations impact Alzheimer's disease (AD) pathology in male mice. Restoring the gut microbiota via fecal microbiota transplantation (FMT) reversed amyloid-beta (Aβ) deposition and associated changes, highlighting microglia's role.
Area of Science:
- Neuroscience
- Microbiology
- Immunology
Background:
- Lifelong antibiotic (ABX) treatment in male APPPS1-21 mice reduces amyloid-beta (Aβ) pathology and alters microglia.
- Gut microbiome dysbiosis is increasingly linked to neurodegenerative diseases like Alzheimer's.
Purpose of the Study:
- To investigate the impact of short-term antibiotic exposure and subsequent fecal microbiota transplantation (FMT) on amyloidosis in young male mice.
- To elucidate the role of microglia in mediating gut microbiome-induced changes in Alzheimer's disease (AD) pathology.
Main Methods:
- Short-term high-dose antibiotic (ABX) treatment in preweaned male mice.
- Fecal microbiota transplantation (FMT) from wild-type (WT) or transgenic (Tg) male donors into ABX-treated mice.
- Transcriptomic analysis and microglia depletion using CSF1R inhibitors.
Main Results:
- A short 7-day ABX treatment reduced Aβ amyloidosis, altered microglia, and degenerative changes in male mice.
- FMT completely restored Aβ pathology and microglia phenotypes in ABX-treated mice.
- Microglia depletion via CSF1R inhibition did not reduce cerebral Aβ amyloidosis in ABX-treated mice, indicating their critical role.
Conclusions:
- Gut microbiome modulation significantly impacts cerebral Aβ deposition in a sex-specific manner.
- Microglia are essential mediators of gut microbiome-driven alterations in Alzheimer's disease pathology.
- FMT can reverse established Aβ amyloidosis and associated neuropathology, suggesting therapeutic potential.
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