Receptor-mediated transport of human amyloid beta-protein 1-40 and 1-42 at the blood-brain barrier

Since amyloid beta-protein (A beta) is the primary component of both vascular and parenchymal amyloid deposits in Alzheimer's disease, information regarding its permeability at the blood-brain barrier (BBB) will help elucidate the contribution of circulating A beta to vascular and parenchymal A beta deposition in this disease and in brain aging. The permeability of the D- and L-enantiomers of A beta 1-40 and L-A beta 1-42 at the BBB was determined in the normal adult rat by quantifying the permeability coefficient-surface area product (PS) for each protein after correction for the residual plasma volume (Vp) occupied by the protein [labeled with a different isotope of iodine (125I vs 131I)] in blood vessels of different brain regions. After a single i.v. bolus injection, the plasma pharmacokinetics determined by TCA precipitation, paper chromatography, and SDS-PAGE were similar for both 125I-L-A beta 1-40 and 125I-L-A beta 1-42. The PS at the BBB for L-A beta 1-42 was significantly (1.4- to 1.8-fold) higher than for L-A beta 1-40 and ranged from 17.7 to 26.4 x 10(-6) ml/g/s for different brain regions. A comparison of the PS values at the BBB for L-A beta 1-40 showed no significant difference when determined at 15 or 30 min after i.v. bolus injection, times that reflect different levels of degradation in plasma (37.9% at 15 min and 65.5% at 30 min). The PS values obtained, therefore, were representative of the intact protein rather than degradation products. The PS values obtained for the all-D-enantiomer of A beta 1-40 were very low and comparable to that of albumin and IgG, whose mechanism of transport is by passive diffusion. Taken together, these data imply a stereoisomer-specific, ligand-receptor interaction at the BBB for the L-A beta proteins. The high PS values observed for L-A beta 1-40 and 1-42 compare to Insulin, whose uptake is decidedly by a receptor-mediated transport process, and suggest a similar mechanism for L-A beta entry into the brain.