IgG depletion by FcRn blockade is associated with changes in amyloid pathology and neurodegeneration in APP/PS1 mice

Abstract Background Autoimmune disorders are associated with an increased risk of developing Alzheimer’s Disease (AD). Dysregulated autoantibodies have been suggested to contribute to exacerbated amyloid-beta (Aβ) accumulation. Based on the potential contribution of humoral immunity to AD pathogenesis, we hypothesized that reducing circulating IgG may influence AD-type pathologies. Methods The neonatal Fc receptor (FcRn) antagonist efgartigimod, approved for the treatment of IgG-mediated autoimmune diseases, can rapidly reduce circulating IgG levels by blocking FcRn-mediated IgG recycling. Eight-month-old female APP/PS1 mice were intraperitoneally injected with efgartigimod at a dose of 10 mg/kg once weekly for 4 weeks or saline as a control. After treatment, the mice were subjected to behavioral tests, pathological examinations, and biochemical analyses to evaluate behavioral phenotypes and AD-type pathologies. In addition, serum from efgartigimod-treated male rats was used to treat SH/APPswe/PS1wt cells to investigate the effects on Aβ metabolism in vitro. Results Efgartigimod effectively reduced serum IgG levels and ameliorated brain IgG deposition. Relative to saline-treated controls, circulating IgG depletion by efgartigimod was associated with better performance in selected behavioral measures and lower brain Aβ burden in APP/PS1 mice. Additionally, efgartigimod treatment was associated with lower levels of Tau phosphorylation, neuroinflammation, and neuronal apoptosis. Compared with control serum, serum from efgartigimod-treated rats was associated with altered Aβ processing and a higher mitochondrial-positive area fraction in vitro. Conclusions This study shows that FcRn blockade depletes circulating IgG and is associated with changes in AD-type pathologies in APP/PS1 mice, supporting further investigation of humoral immunity and FcRn-targeted approaches in AD.