TY - JOUR
T1 - Receptor-mediated transport of human amyloid β-protein 1-40 and 1-42 at the blood-brain barrier
AU - Poduslo, Joseph F.
AU - Curran, Geoffry L.
AU - Sanyal, Bharati
AU - Selkoe, Dennis J.
N1 - Funding Information:
This investigation was supported by NIH Grants NS-35074 (J.F.P.) and AG-12749 (D.J.S.) and by the Mayo Foundation.
PY - 1999/6
Y1 - 1999/6
N2 - 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 (V(p)) 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 x 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.
AB - 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 (V(p)) 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 x 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.
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U2 - 10.1006/nbdi.1999.0238
DO - 10.1006/nbdi.1999.0238
M3 - Article
C2 - 10408808
AN - SCOPUS:0032995727
SN - 0969-9961
VL - 6
SP - 190
EP - 199
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 3
ER -