IgG-assisted age-dependent clearance of Alzheimer's amyloid β peptide by the blood-brain barrier neonatal Fc receptor

The role of blood-brain barrier (BBB) transport in clearance of amyloid β-peptide (Aβ) by Aβ immunotherapy is not fully understood. To address this issue, we studied the effects of peripherally and centrally administered Aβ-specific IgG on BBB influx of circulating Aβ and efflux of brain-derived Aβ in APPsw^+/- mice, a model that develops Alzheimer's disease-like amyloid pathology, and wild-type mice. Our data show that anti-Aβ IgG blocks the BBB influx of circulating Aβ in APPsw^+/- mice and penetrates into the brain to sequester brain Aβ. In young mice, Aβ-anti-Aβ complexes were cleared from brain to blood by transcytosis across the BBB via the neonatal Fc receptor (FcRn) and the low-density lipoprotein receptor-related protein (LRP), whereas in older mice, there was an age-dependent increase in FcRn-mediated IgG-assisted Aβ BBB efflux and a decrease in LRP-mediated clearance of Aβ-anti-Aβ complexes. Inhibition of the FcRn pathway in older APPsw^+/- mice blocked clearance of endogenous Aβ40/42 by centrally administered Aβ immunotherapy. Moreover, deletion of the FcRn gene in wild-type mice inhibited clearance of endogenous mouseAβ40/42 by systemically administered anti-Aβ. Our data suggest that the FcRn pathway at the BBB plays a crucial role in IgG-assisted Aβ removal from the aging brain.