IgG-assisted age-dependent clearance of Alzheimer's amyloid beta peptide by the blood-brain barrier neonatal Fc receptor.
The role of blood-brain barrier (BBB) transport in clearance of amyloid beta-peptide (Abeta) by Abeta immunotherapy is not fully understood. To address this issue, we studied the effects of peripherally and centrally administered Abeta-specific IgG on BBB influx of circulating Abeta and efflux of brain-derived Abeta in APPsw(+/-) mice, a model that develops Alzheimer's disease-like amyloid pathology, and wild-type mice. Our data show that anti-Abeta IgG blocks the BBB influx of circulating Abeta in APPsw(+/-) mice and penetrates into the brain to sequester brain Abeta. In young mice, Abeta-anti-Abeta 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 Abeta BBB efflux and a decrease in LRP-mediated clearance of Abeta-anti-Abeta complexes. Inhibition of the FcRn pathway in older APPsw(+/-) mice blocked clearance of endogenous Abeta40/42 by centrally administered Abeta immunotherapy. Moreover, deletion of the FcRn gene in wild-type mice inhibited clearance of endogenous mouse Abeta40/42 by systemically administered anti-Abeta. Our data suggest that the FcRn pathway at the BBB plays a crucial role in IgG-assisted Abeta removal from the aging brain.
Deane
Rashid
R
Division of Neurovascular Biology, Department of Neurosurgery, Arthur Kornberg Medical Research Building, University of Rochester Medical Center, Rochester, New York 14642, USA.
Sagare
Abhay
A
Hamm
Katie
K
Parisi
Margaret
M
LaRue
Barbra
B
Guo
Huang
H
Wu
Zhenhua
Z
Holtzman
David M
DM
Zlokovic
Berislav V
BV
D000375:Aging / Q000502:physiology*; D000544:Alzheimer Disease / Q000378:metabolism* / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000502:physiology / Q000627:therapeutic use*; D006801:Humans; D007074:Immunoglobulin G / Q000502:physiology / Q000627:therapeutic use*; D007167:Immunotherapy / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism*; D011961:Receptors, Fc / Q000235:genetics / Q000502:physiology / Q000627:therapeutic use*
D016229:Amyloid beta-Peptides; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D010446:Peptide Fragments; D011961:Receptors, Fc; C078592:amyloid beta-protein (1-40); C100688:Fc receptor, neonatal