ALZHEIMER'S RESEARCH PROJECT: Effect of Age on Antibody Diversity

National Institute On Aging

Investigators

Linked publications, trials & patents

Abstract

We examined the effects of aging on naïve B cells participating in an immune response. Splenic follicular B cells from young and old C57BL/6 mice were co-transferred into young muMT recipients and immunized with nitrophenyl-chicken gamma globulin (NP-CGG). Old B cell donors produced lower antibody serum titers to NP than B cells from young mice, even though old B cells were overrepresented in the germinal center response. To characterize these germinal centers formed from young or old B cells, we carried out scRNA-seq and scBCR-seq of germinal centers two weeks after immunization. Analyses of heavy and light chain pairings, clonal lineage reconstruction, and affinity measurements of recombinant antibodies all suggested that germinal centers populated by old B cells have lower affinity germline receptors. Thus, loss of the highest affinity germline pairings results in lower quality antibodies during the initial response. For Alzheimer's research, recent work has implicated the peripheral immune system in the progression of Alzheimer's disease (AD) in both mice and humans. A handful of studies have noted a role for B cells and antibodies in mouse models of AD, however, no group has reported on the reactivity of these antibodies, nor whether specific antibodies promote or slow disease progression. To this end, we have been studying the effect of a restricted repertoire in AD by crossing the MD4 mouse, which only makes antibodies against an irrelevant antigen, with the 5XFAD mouse, which is a popular model of AD. We will measure plaque accumulation and behavioral changes in the mice to determine if the specificity of antibodies is important.