Epitope-Dependent Effects of Beta-Amyloid Antibodies on Beta-Amyloid Clearance in an In Vitro Model of the Blood-Brain Barrier

Objective: To investigate the role of RAGE in the epitope-dependent effects of A beta 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 A beta antibodies or A beta peptide fragments on A beta exchange across the BBB. Results: An N-terminal A beta antibody significantly enhanced the basolateral-to-apical transcytosis of fluorescein-A beta(1-42) across the BBB model (41%), while no effect was apparent with a C-terminal A beta antibody. Interestingly, modulation of RAGE in the presence of a C-terminal A beta antibody resulted in a 65% increase in A beta clearance across the BBB model, suggesting the C-terminal antibody-A beta complex is susceptible to RAGE transport. Additionally, N-terminal peptide fragments of A beta attenuated the brain penetration of full length A beta in the BBB model, indicating the N-terminal region of A beta is required for brain uptake. Conclusions: Antibodies masking the N-terminal region of A beta increase A beta clearance across the BBB by preventing A beta from interacting with the RAGE transporter, whereas antibodies bound to the C-terminus of A beta are taken up by RAGE and, hence, do not influence the BBB clearance of A beta.