Abstract 40: Gut Dysbiosis Exacerbates Neuroinflammation By Activation Of B Cells In A Mouse Model Of Cerebral Amyloid Angiopathy

Abstract

Introduction: Cerebral amyloid angiopathy (CAA) is a debilitating disease that leads to intracerebral hemorrhage, white matter disease, and progressive cognitive decline in patients >50 years of age. Studies investigating the neuroimmune landscape in CAA are sparse. Here, we investigate the role of B cells in CAA. Methods: Pre-symptomatic (2 months) and symptomatic (10-13 months) male Tg-SwDI mice (CAA mice) harboring Swedish, Dutch, and Iowa mutations of human amyloid precursor protein (APP) were used as a mouse model of CAA. Single cells isolated from the brain were analyzed using flow cytometry to characterize neuroinflammation and cognitive impairment was assessed using fear conditioning. Fecal microbiota transplantation (FMT) of the microbiome from pre-symptomatic and symptomatic CAA mice into young wild-type (WT) recipient male mice (2 months) was performed to determine if CAA-induced gut dysbiosis contributes to brain B cell activation. Results: Cognitive assessment using fear conditioning indicated a significantly lower delta inactive state in symptomatic CAA mice (n=4/grp, * P <0.05) compared to pre-symptomatic CAA mice. Symptomatic CAA mice had a significantly lower relative frequency of microglia (CD45 int CD11b + , n=11-13/grp, ** P <0.01) and significant infiltration of lymphoid (CD45 high CD11b - , n=11-13/grp, *** P <0.001) cells in the brain, as compared to pre-symptomatic CAA mice. Symptomatic CAA mice had significantly higher B cells in the brain (n=10-13/grp, * P <0.05. Further, activated B cells as assessed by the expression level of CD11b showed that CD11b + B cells were significantly higher in the symptomatic CAA brain (n=10-13/grp, * P <0.05). Interestingly, this phenotype was recapitulated in young WT recipients reconstituted with pre-symptomatic CAA and CAA microbiome through FMT. Young WT recipients with CAA biome had significantly higher relative frequency of CD11b + B cells in the brain compared to young recipients with pre-CAA biome (n=7-9/grp, *** P <0.001). Conclusions: These results suggest that the aberrant activation of B cells in the brain may be influenced by CAA-induced gut dysbiosis. Further investigations upon the functional role of CD11b + B cells in the vascular deposition of Aβ are warranted.