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The Journal of Neuroscience, December 14, 2005, 25(50):11495-11503; doi:10.1523/JNEUROSCI.3697-05.2005

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Neurobiology of Disease
IgG-Assisted Age-Dependent Clearance of Alzheimer's Amyloid {beta} Peptide by the Blood–Brain Barrier Neonatal Fc Receptor

Rashid Deane,1 * Abhay Sagare,1 * Katie Hamm,1 Margaret Parisi,1 Barbra LaRue,1 Huang Guo,1 Zhenhua Wu,1 David M. Holtzman,2 and Berislav V. Zlokovic1

1Frank P. Smith Laboratories for Neuroscience and Neurosurgical Research, Department of Neurosurgery and Division of Neurovascular Biology, Arthur Kornberg Medical Research Building, University of Rochester Medical Center, Rochester, New York 14642, and 2Departments of Neurology, and Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110

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.

Key words: antibody; amyloid {beta}; Alzheimer's disease; blood–brain barrier; amyloid; transport

Received Sep 1, 2005; revised October 29, 2005; accepted October 30, 2005.






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