PERMEABILITY AND RESIDUAL PLASMA-VOLUME OF HUMAN, DUTCH VARIANT, AND RAT AMYLOID BETA-PROTEIN-1-40 AT THE BLOOD-BRAIN-BARRIER

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-su rface area (PS) product for each protein after correction for the resi dual plasma volume (V-p) 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, whi ch is 130 to 220 times greater than albumin. These high PS values comp are to that of insulin, whose uptake is decidedly by a receptor-mediat ed transport process, and suggest a similar mechanism for A beta. Rema rkably, 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 V-p values of human and ra t A beta were comparable, the Dutch variant was 2 to 3 times higher, i ndicating adherence to the vessel walls in different brain regions, co nsistent with the heavy A beta deposition that has been described in i ntracerebral vessel walls with this variant. The high PS values observ ed for A beta at the BBB suggest that sources outside the nervous syst em could contribute, at least in part, to the cerebral A beta deposits seen in Alzheimer's disease. SDS-PAGE of I-125-labeled human A beta a fter 60 min of uptake revealed intact protein in plasma and in differe nt brain regions. In addition, I-125-labeled human A beta binding to a protein of 67,000 in both plasma and brain tissue regions was observe d with SDS-PAGE. This protein was tentatively identified as albumin, a nd it was not detectable in the brain regions of animals that had unde rgone intracardiac perfusion; hence, a portion of A beta binds tightly to and is likely transported by albumin in plasma. The absence of thi s A beta-albumin complex in brain regions after perfusion and the low permeability of albumin at the BBB imply that A beta itself is efficie ntly transported at the BBB to account for the high PS values, althoug h presentation of A beta to the capillary endothelial cell by albumin or other plasma proteins cannot be excluded. (C) 1997 Academic Press.