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Since amyloid β-protein (Aβ) 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 Aβ to vascular and parenchymal Aβ deposition in this disease and in brain aging. The permeability of the d- and l-enantiomers of Aβ 1–40 and l-Aβ 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 (Vp) occupied by the protein [labeled with a different isotope of iodine (125I vs 131I)] 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 both 125I-l-Aβ 1–40 and 125I-l-Aβ 1–42. The PS at the BBB for l-Aβ 1–42 was significantly (1.4- to 1.8-fold) higher than for l-Aβ 1–40 and ranged from 17.7 to 26.4 × 10−6 ml/g/s for different brain regions. A comparison of the PS values at the BBB for l-Aβ 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 Aβ 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 the l-Aβ proteins. The high PS values observed for l-Aβ 1–40 and 1–42 compare to insulin, whose uptake is decidedly by a receptor-mediated transport process, and suggest a similar mechanism for l-Aβ entry into the brain.