Modulation of amyloid deposition and neuroinflammation by the microbiome

Background Animal models of Alzheimer’s disease (AD) recapitulate the severe amyloidosis and neuroinflammation that is evident in the human disease. It is now well established that inflammation associated with amyloid deposition reflects the activation of astrocytes and microglia in response to injury, but the role of peripheral tissues and more importantly, the microbiota in regulating innate immunity that in turn leads to CNS dysfunction has not, to date been defined. We have tested the hypothesis that the composition of the intestinal microbiome plays a key role in modulating neuro‐inflammation that will ultimately influence amyloid deposition in two established mouse models of Aβ‐amyloidosis. Methods We orally administered a combination of antibiotics to induce rapid and sustained alterations in gut microbial populations in two mouse models of amyloidosis. The antibiotic cocktail was administered either postnatally or throughout the lifetime of the animal prior to cull and we employed IHC, biochemical and molecular assays to evaluate amyloid deposition and neuroinflammation in the mouse models. Newly‐generated germ‐free mouse models are being evaluated. Results Our studies indicate that alterations in the microbiome parallel changes in plasma cytokines and chemokines, reductions in amyloid deposition and modulation of morphological and transcriptional landscapes of microglia. These effects are unique to male, but not female animals. Conclusions Our studies reveal an unexpected, but significant alteration in amyloid deposition and microglial phenotypes in the brains of male transgenic mice upon treatment with orally administered antibiotics. 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.