Lack of brain-to-blood efflux transport activity of low-density lipoprotein receptor-related protein-1 (LRP-1) for amyloid-beta peptide(1-40) in mouse: involvement of an LRP-1-independent pathway.
The contribution of low-density lipoprotein receptor-related protein-1 (LRP-1) to the brain-to-blood amyloid-beta peptide (A beta) efflux transport across the blood-brain barrier (BBB) remains controversial. The purpose of the present study was to clarify whether or not LRP-1 plays a role in efflux transport of A beta at the BBB. After microinjection of [(125)I]activated alpha2-macroglobulin (alpha 2M), a typical LRP-1 ligand, into mouse secondary somatosensory cortex region under ketamine-xylazine anesthesia, residual radioactivity was not significantly decreased up to 90 min, whereas after microinjection of [(125)I]human A beta(1-40) [hA beta(1-40)], the residual radioactivity decreased time-dependently. Co-administration of receptor-associated protein, an inhibitor of LRP-1, did not influence [(125)I]hA beta(1-40) elimination from mouse brain, suggesting that members of the LDL receptor gene family, including LRP-1, do not contribute to hA beta(1-40) elimination from mouse brain across the BBB. There was no significant difference between the uptakes of [(125)I]activated alpha 2M and [(14)C]inulin by mouse brain slices, suggesting that activated alpha 2M was not significantly bound to and/or taken up by parenchymal cells. In conclusion, our results show that LRP-1 does not play a significant role in the brain-to-blood efflux transport of A beta(1-40) at the mouse BBB, but an unidentified transporter(s) appears to be involved.
Ito
Shingo
S
Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, Japan.
Ueno
Takashi
T
Ohtsuki
Sumio
S
Terasaki
Tetsuya
T
D000465:Algorithms; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001693:Biological Transport, Active / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D006801:Humans; D007202:Indicators and Reagents; D007457:Iodine Radioisotopes; D008099:Liver / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008297:Male; D008744:Methylamines / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000378:metabolism*; D011973:Receptors, LDL; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000494:pharmacology*; D000511:alpha-Macroglobulins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D007202:Indicators and Reagents; D007457:Iodine Radioisotopes; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D008744:Methylamines; D010446:Peptide Fragments; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; D000511:alpha-Macroglobulins; C078592:amyloid beta-protein (1-40); C027451:methylamine