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.
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.
Authors: Corbin Bachmeier; David Beaulieu-Abdelahad; Fiona Crawford; Michael Mullan; Daniel Paris Journal: J Mol Neurosci Date: 2012-08-14 Impact factor: 3.444