Abstract Body

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

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. In parallel, rederivation of the APPPS1-21 transgenic mouse model yielded germ-free mice that are devoid of microbiota. 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. Microglia play a critical role in modulation of these phenotypes. Finally, amyloid deposition and microglial phenotypes in both male and female animals is significantly altered in GF mice compared with mice raised in SPF conditions.

Conclusion: Our studies reveal sex-specific alterations in amyloid deposition and microglial phenotypes in transgenic mice upon treatment with orally administered ABX.

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