TY - JOUR
T1 - Functional characterization of the brain-to-blood efflux clearance of human amyloid-β peptide (1-40) across the rat blood-brain barrier
AU - Ito, Shingo
AU - Ohtsuki, Sumio
AU - Terasaki, Tetsuya
N1 - Funding Information:
The authors would like to thank Drs. T. Iwatsubo and T. Hashimoto for valuable discussions, and Ms. N. Funayama for secretarial assistance. This study was supported in part by a Grant-in-Aid for Scientific Research on Priority Areas 17025005 from The Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, and a 21st Century Center of Excellence (COE) Program grant from the Japan Society for the Promotion of Science.
PY - 2006/11
Y1 - 2006/11
N2 - The present study sought to characterize the brain-to-blood efflux transport of human amyloid-β peptide (hAβ)(1-40) across the blood-brain barrier (BBB) in rats. We determined the apparent brain-to-blood [125I]hAβ(1-40) efflux clearance in rats and found it to be 11.0 μL/(min g brain). There were no significant gender differences in the apparent brain-to-blood [125I]hAβ(1-40) efflux clearance. The brain-to-blood [125I]hAβ(1-40) efflux transport was significantly inhibited by unlabeled hAβ(1-40) and hAβ(1-42) by 79.1% and 36.4%, respectively, but was not inhibited by hAβ(1-43) and hAβ(40-1), and was significantly facilitated by hAβ(17-40) by 16.0%, which is one of the major proteolytic fragments of hAβ(1-40) generated by the action of Aβ degradation enzymes, such as endothelin-converting enzyme. Pre-administration of human receptor-associated protein, a low-density lipoprotein receptor-related protein (LRP) antagonist, reduced the elimination of [125I]hAβ(1-40) by 20.3%, while quinidine or verapamil, P-glycoprotein (P-gp) inhibitors, did not significantly affect the elimination. Western blot analysis suggested that LRP-1 is expressed in rat brain capillary endothelial cells. In conclusion, the partial contribution of LRP-1 and the minor contribution of P-gp suggest that the hAβ(1-40) elimination from rat brain is mediated by as yet unidentified molecules.
AB - The present study sought to characterize the brain-to-blood efflux transport of human amyloid-β peptide (hAβ)(1-40) across the blood-brain barrier (BBB) in rats. We determined the apparent brain-to-blood [125I]hAβ(1-40) efflux clearance in rats and found it to be 11.0 μL/(min g brain). There were no significant gender differences in the apparent brain-to-blood [125I]hAβ(1-40) efflux clearance. The brain-to-blood [125I]hAβ(1-40) efflux transport was significantly inhibited by unlabeled hAβ(1-40) and hAβ(1-42) by 79.1% and 36.4%, respectively, but was not inhibited by hAβ(1-43) and hAβ(40-1), and was significantly facilitated by hAβ(17-40) by 16.0%, which is one of the major proteolytic fragments of hAβ(1-40) generated by the action of Aβ degradation enzymes, such as endothelin-converting enzyme. Pre-administration of human receptor-associated protein, a low-density lipoprotein receptor-related protein (LRP) antagonist, reduced the elimination of [125I]hAβ(1-40) by 20.3%, while quinidine or verapamil, P-glycoprotein (P-gp) inhibitors, did not significantly affect the elimination. Western blot analysis suggested that LRP-1 is expressed in rat brain capillary endothelial cells. In conclusion, the partial contribution of LRP-1 and the minor contribution of P-gp suggest that the hAβ(1-40) elimination from rat brain is mediated by as yet unidentified molecules.
KW - Alzheimer's disease
KW - Aβ degrading enzyme
KW - Efflux transport
KW - Gender difference
KW - LRP-1
KW - P-gp
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U2 - 10.1016/j.neures.2006.07.006
DO - 10.1016/j.neures.2006.07.006
M3 - Article
C2 - 16926058
AN - SCOPUS:33750017850
VL - 56
SP - 246
EP - 252
JO - Neuroscience Research
JF - Neuroscience Research
SN - 0168-0102
IS - 3
ER -