Insights into the mechanisms of action of anti-Aβ antibodies in Alzheimer's disease mouse models

Yona Levites, Lisa A. Smithson, Robert W. Price, Rachel S. Dakin, Bin Yuan, Michael R. Sierks, Jungsu Kim, Eileen McGowan, Kim Reed Dana, Terrone L. Rosenberry, Pritam Das, Todd E. Golde

Research output: Contribution to journalArticle

92 Scopus citations

Abstract

A number of hypotheses regarding how anti-Aβ antibodies alter amyloid deposition have been postulated, yet there is no consensus as to how Aβ immunotherapy works. We have examined the in vivo binding properties, pharmacokinetics, brain penetrance, and alterations in Aβ levels after a single peripheral dose of anti-Aβ antibodies to both wild-type (WT) and young non-Aβ depositing APP and BRI-Aβ42 mice. The rapid rise in plasma Aβ observed after antibody (Ab) administration is attributable to prolongation of the half-life of Aβ bound to the Ab. Only a miniscule fraction of Ab enters the brain, and despite dramatic increases in plasma Aβ, we find no evidence that total brain Aβ levels are significantly altered. Surprisingly, cerebral spinal fluid Aβ levels transiently rise, and when Ab:Aβ complex is directly injected into the lateral ventricles of mice, it is rapidly cleared from the brain into the plasma where it remains stable. When viewed in context of daily turnover of Aβ, these data provide a framework to evaluate proposed mechanisms of Aβ attenuation mediated by peripheral administration of an anti-Aβ monoclonal antibody (mAb) effective in passive immunization paradigm. Such quantitative data suggest that the mAbs are either indirectly enhancing clearance of Aβ or targeting a low abundance aggregation intermediate.

Original languageEnglish (US)
Pages (from-to)E2002-E2014
JournalFASEB Journal
Volume20
Issue number14
DOIs
StatePublished - Dec 1 2006

Keywords

  • Amyloid deposits
  • Immune complex

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Fingerprint Dive into the research topics of 'Insights into the mechanisms of action of anti-Aβ antibodies in Alzheimer's disease mouse models'. Together they form a unique fingerprint.

  • Cite this

    Levites, Y., Smithson, L. A., Price, R. W., Dakin, R. S., Yuan, B., Sierks, M. R., Kim, J., McGowan, E., Dana, K. R., Rosenberry, T. L., Das, P., & Golde, T. E. (2006). Insights into the mechanisms of action of anti-Aβ antibodies in Alzheimer's disease mouse models. FASEB Journal, 20(14), E2002-E2014. https://doi.org/10.1096/fj.06-6463fje