Abstract Body

Background: We have explored the role of the gut microbiome on Abeta deposition and microglial transcriptomes in transgenic mouse models of Abeta amyloidosis using antibiotic (ABX)-mediated perturbations of the gut microbiota.

Methods: We orally administered an antibiotic cocktail either postnatally or throughout life to induce sustained alterations in gut microbial populations in two mouse models of Abeta amyloidosis. Using well-established IHC, biochemical and transcriptional readouts, we have evaluated amyloid deposition and neuroinflammation in these paradigms.

Result: We demonstrate that ABX-mediated alterations in the microbiome parallel changes in plasma cytokines and chemokines, reductions in amyloid deposition and modulation of morphological and transcriptional landscapes of microglia that is selective for male animals. Importantly, reintroduction of fecal matter (FMT) into ABX-treated male mice restores amyloid pathology, neurodegenerative phenotypes and transcriptional changes to levels that observed in vehicle-treated mice. We have performed ovariectomies (OVX) of female mice to reduce levels of ovarian hormones and have demonstrated that the gut microbiome is perturbed in this setting that parallels reductions in Abeta burden. Furthermore, OVX treated female mice supplemented with b-estradiol in the drinking water restores Abeta burden and microglial phenotypes.

Conclusion: Our studies reveal that ovarian hormones play a central role in mediating the sex-specific alterations in microbiome composition, amyloid deposition and microglial phenotypes in transgenic mice.

Acknowledgments: This work was supported by Cure Alzheimer’s Fund (CAF), Open Philanthropy Fund, Bright Focus Foundation, Alzheimer’s Association and Good Ventures Foundation. SSS is a paid consultant of Green Valley Pharmaceuticals Inc.