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 beta-peptide (A beta) by A beta immunotherapy is not fully understood. To address this issue, we studied the effects of peripherally and centrally administered A beta-specific IgG on BBB influx of circulating A beta and efflux of brain-derived A beta in APPsw(+/-) mice, a model that develops Alzheimer's disease-like amyloid pathology, and wild-type mice. Our data show that anti-A beta IgG blocks the BBB influx of circulating A beta in APPsw(+/-) mice and penetrates into the brain to sequester brain A beta. In young mice, A beta-anti-A beta 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 A beta BBB efflux and a decrease in LRP-mediated clearance of A beta-anti-A beta complexes. Inhibition of the FcRn pathway in older APPsw(+/-) mice blocked clearance of endogenous A beta 40/42 by centrally administered A beta immunotherapy. Moreover, deletion of the FcRn gene in wild-type mice inhibited clearance of endogenous mouse A beta 40/ 42 by systemically administered anti-A beta. Our data suggest that the FcRn pathway at the BBB plays a crucial role in IgG-assisted A beta removal from the aging brain.