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Microcirculation. 2011 Jul;18(5):373-9. doi: 10.1111/j.1549-8719.2011.00096.x.

Epitope-dependent effects of Beta-amyloid antibodies on Beta-amyloid clearance in an in vitro model of the blood-brain barrier.

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1
The Roskamp Institute, Sarasota, Florida, USA. cbachmeier@rfdn.org

Abstract

OBJECTIVE:

To investigate the role of RAGE in the epitope-dependent effects of Aβ antibodies used as a peripheral sink therapy in AD.

METHODS:

An in vitro model of the BBB was used to examine the effect of various Aβ antibodies or Aβ peptide fragments on Aβ exchange across the BBB.

RESULTS:

An N-terminal Aβ antibody significantly enhanced the basolateral-to-apical transcytosis of fluorescein-Aβ(1-42) across the BBB model (41%), while no effect was apparent with a C-terminal Aβ antibody. Interestingly, modulation of RAGE in the presence of a C-terminal Aβ antibody resulted in a 65% increase in Aβ clearance across the BBB model, suggesting the C-terminal antibody-Aβ complex is susceptible to RAGE transport. Additionally, N-terminal peptide fragments of Aβ attenuated the brain penetration of full length Aβ in the BBB model, indicating the N-terminal region of Aβ is required for brain uptake.

CONCLUSIONS:

Antibodies masking the N-terminal region of Aβ increase Aβ clearance across the BBB by preventing Aβ from interacting with the RAGE transporter, whereas antibodies bound to the C-terminus of Aβ are taken up by RAGE and, hence, do not influence the BBB clearance of Aβ.

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