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Mechanisms By Which the Gut Microbiome Influences Amyloid Deposition and Neuroinflammation in Mouse Models of Alzheimer’s Disease

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In our earlier proposal, we tested the hypothesis that the composition of the intestinal microbiome might play a key role in modulating neuroinflammation that, in turn, influences Abeta deposition. We have demonstrated that long-term treatment with an antibiotic (ABX) cocktail does not alter total bacterial abundance in either the cecum or feces, but rather, induces a distinct perturbation in gut microbial diversity. The alterations in bacterial diversity are paralleled by selective changes in the levels of several circulating cytokines/chemokines in the blood sera. More importantly, we demonstrate that amyloid plaque deposition and plaque size are significantly reduced in the brains of male ABX-treated animals that is co-incident with an elevation in soluble Abeta peptides. Finally, ABX-induced perturbations in gut microbial diversity also influenced neuroinflammatory responses by conferring reduced plaque-localized gliosis and altered microglial morphology. Collectively, our findings indicate that the gut microbial composition regulates neuroinflammatory responses in the brain that ultimately can attenuate Abeta deposition.

These studies serve as the foundation for our current proposal, in which we seek to define the mechanism(s) by which alterations in microbial diversity affect amyloid deposition and neuroinflammation. We now propose to investigate the role of the microbiome in modulating neuroinflammation, microglial phenotypes and Abeta pathology in an independent APPSWE/PS1L166P transgenic mouse model in which the transgenes are driven by a neuronal-specific Thy1 promoter. In addition, we will determine whether ABX-induced alterations in gut microbial community structure translate to alterations in specific metabolites (e.g., short chain fatty acids (SCFAs)) in APPSWE/PS1L166P and APPSWE/PS1ΔE9 mice. Finally, we will assess amyloidosis and neuroinflammation in germ-free APPSWE/PS1ΔE9 and APPSWE/PS1L166P mice and ascertain if reconstitution of the gut with microbial populations or microbial metabolites can alter phenotypes.