Gut Immunity, Neurovascular Dysregulation and Cognitive Impairment

Alzheimer’s disease and related dementias (ADRDs) are a group of age-related diseases affecting cognitive function for which no treatments are available. Neuroinflammation and neurovascular dysfunction have emerged as crucial drivers of disease progression in ADRDs. In particular, cerebral endothelial cells and microglia, brain resident innate-immune cells, have been implicated in the accumulation of hyperphosphorylated tau, a microtubule associated protein and a key feature of ADRD’s pathology. Dysregulation of the peripheral immune system could also play a role and may influence endothelial and microglial function contributing to cognitive impairment. However, how the peripheral immune system communicates with the cerebral microvasculature and microglia to alter cognitive function remains to be fully established. IL17-producing T-helper lymphocytes (Th17 cells), a subset of T-helper lymphocytes, and their signature cytokine, IL17, have been implicated in the mechanisms of cognitive impairment. Previous data indicate that circulating Th17-derived IL17 acts on cerebral endothelial cells to induce a deficit in endothelial nitric oxide (NO) promoting tau accumulation and cognitive impairment. Due to their abundance in the gut, Th17 cells are particularly sensitive to gut bacteria and alterations in the gut flora are associated with dysregulation of Th17 cells. Segmented filamentous bacteria (SFB) are commensal bacteria which potently induce gut Th17 cells in mice and alter the course of models of Th17 cell-associated diseases. Therefore, gut Th17 dysregulation induced by SFB could be used as a model to gain a better mechanistic understanding of how gut Th17 cells alter brain health. On these bases, we propose to test the central hypothesis that dysregulation of gut Th17 cells, induced by colonization of the small intestine with SFB, promotes an IL17-mediated inflammatory response in cerebral endothelial cells which, in turn, activates microglia, leading to tau accumulation and cognitive impairment. To this end, the present grant application will examine endothelial function, tau pathology and cognitive function in a mouse model of SFB colonization to test the following hypotheses in male, female and aging mice: (1) Gut SFB colonization promotes gut Th17 differentiation, increases circulating IL17 and induces cerebrovascular and cognitive impairment; (2) Circulating IL17 mediates cerebrovascular dysfunction and cognitive impairment through activation of brain endothelial IL17 receptors; (3) IL17-induced endothelial pro-inflammatory mediators activate microglia leading to tau accumulation and cognitive impairment. The proposed studies fill an obvious gap in the understanding of the effects of gut microbiota on cognition and of the role of circulating IL17, endothelial cells and microglia in mediating these effects. Furthermore, these findings may unveil a novel link between microbiota-induced dysregulation of intestinal Th17 cells, brain tau accumulation and cognitive impairment, with potential public health implications.