Abstract WP140: The Effect of Age-related Gut Dysbiosis on Microglial Function in Cerebral Amyloid Angiopathy

Abstract

The role of “gut-immune-brain axis” across our lifespan is well recognized as a biologic variable. As our populations age, so does the prevalence of age-related illnesses including stroke and its sequelae. We examined how manipulating the microbiome alters the natural history of cerebral amyloid angiopathy (CAA), a major cause of recurring brain hemorrhages, stroke, and cognitive decline. Microglial phenotype changes with aging and deficits in microglial phagocytosis lead to increased amyloid burden in animal models of Alzheimer’s but it is not known if this occurs in CAA. We hypothesize that age-related dysbiosis accelerates initiation and progression of CAA and this effect is mediated by failure of microglial amyloid phagocytosis (MAP). We have investigated the effects of dysbiosis on MAP and cognitive decline in wild-type (WT) and Tg2576 transgenic mice. Gut microbiomes were altered in pre- and post-symptomatic transgenic mice via fecal microbiota transfer (FMT) from young and aged WT mice. Cognitive decline and microglial phenotype were assessed using behavioral tests and flow cytometry. Function of microglia using in vitro primary and ex vivo sorted cultures from CAA mice were also examined. Our preliminary data shows: 1) An increased Firmicutes:Bacteroidetes ratio, indicative of an aging microbiome, occurred in young recipients given aged donor FMT; conversely, the ratio decreased in aged mice given young biome(P<0.001, n=14); 2) Microglial phagocytosis was impaired in aged WT microglia (n=7/gp, P<0.01); and 3) Motor strength in both young and aged WT mice after FMT (n=17/gp) were dependent on the age of the donor microbiome rather than the age of the host (P<0.001). Our studies demonstrate an important role for the gut microbiome in modulating CAA pathogenesis and progression in the brain. Thus, manipulation of the gut microbiota could be an effective therapy to delay the onset and/or slow the progression of disease in CAA patients.