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

Rashid Deane, Abhay Sagare, Katie Hamm, Margaret Parisi, Barbra LaRue, Huang Guo, Zhenhua Wu, David M. Holtzman, Berislav V. Zlokovic

Research output: Contribution to journalArticlepeer-review

193 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)11495-11503
Number of pages9
JournalJournal of Neuroscience
Volume25
Issue number50
DOIs
StatePublished - Dec 14 2005

Keywords

  • Alzheimer's disease
  • Amyloid
  • Amyloid β
  • Antibody
  • Blood-brain barrier
  • Transport

Fingerprint

Dive into the research topics of 'IgG-assisted age-dependent clearance of Alzheimer's amyloid β peptide by the blood-brain barrier neonatal Fc receptor'. Together they form a unique fingerprint.

Cite this