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First published online 21 September 2004
doi: 10.1242/jcs.01381

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Efficient transfer of receptor-associated protein (RAP) across the blood-brain barrier

¹ Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge, LA 70808, USA
² BioMarin Pharmaceutical Incorporated, 371 Bel Marin Keys Boulevard, Suite 210, Novato, CA 94949, USA
³ Department of Pediatrics, and Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA
⁴ Department of Molecular Biopharmacy and Genetics, Tohoku University, 1-1 katahira 2-chome, Aoba-ku, Sendai, 980-8577, Japan

View larger version (10K): [in a new window]   Fig. 1. Serum disappearance pattern of receptor-associated protein (RAP). The four groups represent different doses of [125I]-RAP delivered intravenously in a bolus at time zero. In each group, different mice were studied at various time points, and the serum decay pattern was used to calculate exposure time, the theoretical steady-state time for the integral of serum radioactivity.

View larger version (13K): [in a new window]   Fig. 2 he blood-to-brain transfer of [125I]-RAP had a linear regression correlation with study time for each of the four groups as in Fig. 1, in which different amounts of radioactivity were administered to the mice.

View larger version (11K): [in a new window]   Fig. 3 . In situ brain perfusion of [125I]-RAP, [125I]-melanotransferrin and [99mTc]-albumin. [125I]-RAP had a higher influx transfer constant into the mouse brain when compared with that of [125I]-melanotransferrin and the paracellular permeability marker [99mTc]-albumin.

View larger version (13K): [in a new window]   Fig. 4. Hyoglossus muscle was used as a positive control to determine the influx transfer constant of [125I]-RAP during in situ brain perfusion. The value was higher for [125I]-RAP when compared with that of [125I]melanotransferrin and the paracellular permeability marker [99mTc]-albumin.

View larger version (17K): [in a new window]   Fig. 5. In situ brain perfusion of [125I]-RAP and [125I]-transferrin. [125I] ratio in brain and perfusate were measured over 5 minutes. RAP had greater permeability across the blood-brain barrier into both cortical and subcortical areas than transferrin.

View larger version (18K): [in a new window]   Fig. 6. The uptake of [125I]-RAP by brain parenchyma was greater than that in the capillaries and that of [99mTc]-albumin, and was inhibited by excess RAP. This indicates the presence of a saturable transport system. *Significant difference (P<0.05) in reactivity ratio between parenchymal [125I]-RAP and inhibited [125I]-RAP groups.

View larger version (14K): [in a new window]   Fig. 7. Basolateral-to-apical [125I]-RAP ratio over time in megalin (MEGt) and LDL receptor-related protein (LRPt) transfected MDCK cells and control MDCK cells. Although non-transfected MDCK cells had a basal, saturable apical-to-basolateral flux of [125I]-RAP, overexpression of the chimeric receptor containing the cytoplasmic tail of megalin significantly enhanced this flux, which remained saturable.

View larger version (17K): [in a new window]   Fig. 8. Apical-to-basolateral [125I]-RAP ratio over time in megalin (MEGt) and LDL receptor-related protein (LRPt) transfected MDCK cells and control MDCK cells. Basolateral-to-apical efflux of 125I-RAP was significantly lower than the influx and further reduced by stable transfection of LRPt or MEGt.

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