Receptor-Mediated Transport of Human Amyloid &bgr;-Protein 1–40 and 1–42 at the Blood–Brain Barrier

Author： Poduslo J.F. Curran G.L. Sanyal B. Selkoe D.J.

ISSN： 0969-9961

Source： Neurobiology of Disease, Vol.6, Iss.3, 1999-06, pp. : 190-199

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Abstract

Since amyloid &bgr;-protein (A&bgr;) 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&bgr; to vascular and parenchymal A&bgr; deposition in this disease and in brain aging. The permeability of thed- andl-enantiomers of A&bgr; 1–40 andl-A&bgr; 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 (V_p) occupied by the protein [labeled with a different isotope of iodine (¹²⁵I vs¹³¹I)] in blood vessels of different brain regions. After a single iv bolus injection, the plasma pharmacokinetics determined by TCA precipitation, paper chromatography, and SDS–PAGE were similar for both¹²⁵I-l-A&bgr; 1–40 and¹²⁵I-l-A&bgr; 1–42. The PS at the BBB forl-A&bgr; 1–42 was significantly (1.4- to 1.8-fold) higher than forl-A&bgr; 1–40 and ranged from 17.7 to 26.4 × 10^-6ml/g/s for different brain regions. A comparison of the PS values at the BBB forl-A&bgr; 1–40 showed no significant difference when determined at 15 or 30 min after iv 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&bgr; 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 thel-A&bgr; proteins. The high PS values observed forl-A&bgr; 1–40 and 1–42 compare to insulin, whose uptake is decidedly by a receptor-mediated transport process, and suggest a similar mechanism forl-A&bgr;entry into the brain.