Aberrant B Cell Responses Promote Neuroinflammation In Mice With Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy (CAA) is a small vessel disease, characterized by amyloid beta deposition in the cerebral vasculature. CAA increases the incidence of hemorrhagic stroke and dementia in the elderly. Evidence has revealed that aging alone induces disruption in B cell differentiation and immunosenescence by promoting the presence of age-associated B cells (ABCs) characterized by an upregulation of CD11b high . However, little is known on how these ABCs influence the neuroimmune landscape of vascular dementia, an immune-mediated age-associated disease. Hypothesis: CAA induces the differentiation of B cells in the brain resulting in neuroinflammation characterized by an exacerbated presence of microglia and lymphocytic infiltration. Pre-symptomatic (2mo) and symptomatic (18mo) Tg-SwDI (harboring Swedish, Dutch, and Iowa) mutations of human amyloid precursor protein male mice were used as a model of CAA. Through flow cytometry, we investigated the role of CD11b high B cells in promoting neuroinflammation in CAA. Age-matched C57BL/6 wild-type (WT) male mice were included to determine CAA-specific effects. Results: A remarkably heterogeneous CD19 + B cell population was identified in symptomatic CAA mice. Interestingly, CD19 + CD11b high B cells were significantly increased in the symptomatic CAA brain (n=4-6/gp, P =<0.0001) as compared to pre-symptomatic and age-matched WT mice. Protein expression of CD73, CD80, and CD138 was assessed to determine memory formation, antibody production, and inflammatory properties of these CD19 + CD11b high B cells. Notably, CD19 + CD11b high B cells from CAA symptomatic mice had significantly lower expression of CD73 (n=4-6/gp, P =0.0004), CD80 (n=4-6/gp, P =0.0007), and CD138 (n=4-6/gp, P =0.0154) compared with those CD19 + CD11b high B cells from age-matched WT brain. Finally, CAA mice had significantly higher microglial counts (n=4-6/gp, P =0.0013) and lymphocytic infiltration (n=4-6/gp, P =0.0071) in the brain as compared to pre-symptomatic and WT aged mice. Here, we highlight the diversity of B cells in age-associated vascular dementia. Our data give us further perception into the influence of humoral immunity mediated by ABCs and their immune crosstalk in CAA.