The permeability of normal human, the human Dutch variant, and the rat A beta 1-40 proteins at the blood-brain barrier (BBB) was determined in the normal adult rat by quantifying the permeability coefficient-surface area (PS) product for each protein after correction for the residual plasma volume (Vp) occupied by the protein in the blood vessels of different brain regions. The PS for normal and Dutch A beta ranged from 13 x 10(-6) to 22 x 10(-6) ml/g/s in different brain regions, which is 130 to 220 times greater than albumin. These high PS values compare to that of insulin, whose uptake is decidedly by a receptor-mediated transport process, and suggest a similar mechanism for A beta. Remarkably, the PS for rat A beta was 4 times higher and ranged from 54 x 10(-6) to 82 x 10(-6) ml/g/s for different brain regions, suggesting a distinctive species specificity. While the Vp values of human and rat A beta were comparable, the Dutch variant was 2 to 3 times higher, indicating adherence to the vessel walls in different brain regions, consistent with the heavy A beta deposition that has been described in intracerebral vessel walls with this variant. The high PS values observed for A beta at the BBB suggest that sources outside the nervous system could contribute, at least in part, to the cerebral A beta deposits seen in Alzheimer's disease. SDS-PAGE of 125I-labeled human A beta after 60 min of uptake revealed intact protein in plasma and in different brain regions. In addition, 125I-labeled human A beta binding to a protein of 67,000 in both plasma and brain tissue regions was observed with SDS-PAGE. This protein was tentatively identified as albumin, and it was not detectable in the brain regions of animals that had undergone intracardiac perfusion; hence, a portion of A beta binds tightly to and is likely transported by albumin in plasma. The absence of this A beta-albumin complex in brain regions after perfusion and the low permeability of albumin at the BBB imply that A beta itself is efficiently transported at the BBB to account for the high PS values, although presentation of A beta to the capillary endothelial cell by albumin or other plasma proteins cannot be excluded.