Microbial dysbiosis as a driver of neuroinflammation and pathology in Alzheimer's disease

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ABSTRACT Recent advances have helped to uncover critical roles for gut microbiota in a spectrum of neurological disorders including many neurodegenerative diseases. In the case of Alzheimer’s disease (AD), it has been shown in both AD patients and animal models that neurodegenerative disease progression is associated with large-scale changes in gut microbiota composition. Moreover, recent data also suggest that ablation of the microbiome with either germ-free re-derivation or chronic treatment with broad-spectrum antibiotics water limits amyloidosis in mice that over-express amyloid beta (Ab). While these findings have led to excitement over the potential role for microbial dysbiosis in AD, numerous fundamental questions still remain to be answered on this topic. For one, all of these previous studies have only explored the impact of the murine microbiome on neurodegenerative disease and have not investigated how the specific dysbiosis seen in AD patients affects neurological disease progression. Given the major differences that exist between the mouse and human microbiome, it will be important to specifically probe how alterations in human gut microbiota influence neurodegenerative disease processes. In addition, little is currently known regarding how microbial dysbiosis affects tauopathy. To fill these gaps in knowledge, we will transplant gut microbiota from either AD patients or age- and sex-matched controls into germ-free 3xTg-AD mice, which is a well-described mouse model of AD that develops age-related and progressive Ab-induced neurological disease and tauopathy. The impact of human AD-associated dysbiosis on disease progression will then be determined by evaluating Ab deposition, tauopathy, neurodegeneration, neuroinflammation, and cognitive performance (Aim 1). Recent studies in other non-AD models of neurodegenerative disease suggest that the gut microbiota can influence disease progression via modulation of the immune system and/or by promoting changes in metabolite generation. Therefore, in our second Aim, we will next leverage cutting-edge single-cell RNA-sequencing (scRNA-seq) and metabolomics approaches to provide a comprehensive and unbiased assessment of how AD-associated dysbiosis affects immune responses and the metabolome in our human microbiota transplantation AD mouse model. Our overarching hypothesis is that microbial dysbiosis in AD patients leads to exacerbated neurodegenerative disease progression and that this is associated with dysregulation of immune responses and the metabolome. Successful completion of these proposed research directions will break new ground in our understanding of the role of AD-associated dysbiosis in neurodegenerative disease pathogenesis and will also begin to reveal prospective factors underpinning the effects of the human AD microbiome on disease progression. Furthermore, findings from these studies are of potential translational significance as they could help to establish the microbiome as a therapeutic target to pursue in the treatment of AD.