Gut microbiota-driven brain Aβ amyloidosis in mice requires microglia

Dodiya et al. characterize an APPPS1-21 mouse model of A beta amyloidosis with an antibiotic-perturbed microbiome. Fecal transplantation approaches and microglial depletion studies are employed to establish the causality between the gut microbiota, microglia, A beta, and neurodegeneration. We previously demonstrated that lifelong antibiotic (ABX) perturbations of the gut microbiome in male APPPS1-21 mice lead to reductions in amyloid beta (A beta) 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 A beta amyloidosis, plaque-localized microglia morphologies, and A beta-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 A beta amyloidosis, plaque-localized microglia morphologies, and A beta-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 A beta amyloidosis. Thus, microglia play a critical role in driving gut microbiome-mediated alterations of cerebral A beta deposition.

Automated summary

Researchers characterized a mouse model of A beta amyloidosis with a perturbed microbiome and demonstrated the causality between gut microbiota, microglia, A beta, and neurodegeneration using fecal transplantation approaches and microglial depletion studies. They found that short-term high-dose antibiotic treatment in preweaned male mice led to reductions in A beta amyloidosis and degenerative changes, and fecal microbiota transplantation from donor mice restored these changes. Microglia play a critical role in driving gut microbiome-mediated alterations of cerebral A beta deposition.