Permeability and Residual Plasma Volume of Human, Dutch Variant, and Rat Amyloid &bgr;-Protein 1-40 at the Blood–Brain Barrier

Author： Poduslo J.F. Curran G.L. Haggard J.J. Biere A.L. Selkoe D.J.

Publisher： Academic Press

ISSN： 0969-9961

Source： Neurobiology of Disease, Vol.4, Iss.1, 1997-01, pp. : 27-34

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Abstract

The permeability of normal human, the human Dutch variant, and the rat A&bgr; 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 (V_p) occupied by the protein in the blood vessels of different brain regions. The PS for normal and Dutch A&bgr; 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 A&bgr;. Remarkably, the PS for rat A&bgr; 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 theV_pvalues of human and rat A&bgr; 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&bgr; deposition that has been described in intracerebral vessel walls with this variant. The high PS values observed for A&bgr; at the BBB suggest that sources outside the nervous system could contribute, at least in part, to the cerebral A&bgr; deposits seen in Alzheimer's disease. SDS–PAGE of¹²⁵I-labeled human A&bgr; after 60 min of uptake revealed intact protein in plasma and in different brain regions. In addition,¹²⁵I-labeled human A&bgr; 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&bgr; binds tightly to and is likely transported by albumin in plasma. The absence of this A&bgr;–albumin complex in brain regions after perfusion and the low permeability of albumin at the BBB imply that A&bgr; itself is efficiently transported at the BBB to account for the high PS values, although presentation of A&bgr; to the capillary endothelial cell by albumin or other plasma proteins cannot be excluded.