Gut Microbiota, Endothelial Dysfunction and Tau-Mediated Cognitive Impairment

Bacteria colonizing the mucosal surfaces of our body have a profound effect on the cells of the immune system. In particular, due to the abundance of immune cells in the gut, gut bacteria can influence the immune system of the entire body. Therefore, alterations in gut bacteria can result in dysregulation of immune cells that can cause damage to other organs, including the brain. Indeed, alterations in the gut flora have been implicated in the brain pathology underlying Alzheimer’s disease (AD), but how that happens has not been elucidated. A certain class of gut immune cells (Th17 lymphocytes) are particularly sensitive to gut bacteria and play a major role in autoimmune diseases by producing the harmful cytokine IL-17. IL-17 also can result in the accumulation of the protein tau in the brain, a major culprit in AD. Therefore, this proposal will test the hypothesis that changes in gut bacteria that promote proliferation of Th17 cells in the gut lead to an increase in circulating IL-17 that causes cognitive impairment by promoting accumulation of tau in the brain. To this end, we will colonize the gut of mice with bacteria that activate the proliferation of Th17 cells (segmented filamentous bacteria) to determine whether the increase in IL-17 in the blood will lead to tau accumulation in the brain. The results of these studies will provide a direct link between gut bacteria and tau pathology, and may open new avenues for the treatments of AD and related tauopathies based on modulation of the gut flora.