The permeability of normal human, the human Dutch variant, and the rat Aβ 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 Aβ ranged from 13 × 10−6to 22 × 10−6ml/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 Aβ. Remarkably, the PS for rat Aβ was 4 times higher and ranged from 54 × 10−6to 82 × 10−6ml/g/s for different brain regions, suggesting a distinctive species specificity. While theVpvalues of human and rat Aβ 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 Aβ deposition that has been described in intracerebral vessel walls with this variant. The high PS values observed for Aβ at the BBB suggest that sources outside the nervous system could contribute, at least in part, to the cerebral Aβ deposits seen in Alzheimer's disease. SDS–PAGE of125I-labeled human Aβ after 60 min of uptake revealed intact protein in plasma and in different brain regions. In addition,125I-labeled human Aβ 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 Aβ binds tightly to and is likely transported by albumin in plasma. The absence of this Aβ–albumin complex in brain regions after perfusion and the low permeability of albumin at the BBB imply that Aβ itself is efficiently transported at the BBB to account for the high PS values, although presentation of ...