title: Amyloid-β peptide(1-40) elimination from cerebrospinal fluid involves low-density lipoprotein receptor-related protein 1 at the blood-cerebrospinal fluid barrier.
abstract: Amyloid-β peptide (Aβ) concentration in CSF is potentially a diagnostic and therapeutic target for Alzheimer's disease (AD). The purpose of this study was to clarify the elimination mechanism of human Aβ(1-40) [hAβ (1-40)] from CSF. After intracerebroventricular (ICV) administration, [(125) I]hAβ(1-40) was eliminated from the rat CSF with a half-life of 17.3 min. The elimination of [(125) I]hAβ(1-40) was significantly inhibited by human receptor-associated protein (RAP) and the elimination was attenuated in either anti-low-density lipoprotein receptor-related protein (LRP)1 antibody-treated or RAP-deficient mice, suggesting that a member(s) of the low-density lipoprotein receptor gene family is involved in the elimination of hAβ(1-40) from CSF. The amounts of LRP1 and LRP2 proteins were determined by means of liquid chromatography-tandem mass spectrometry, and the LRP1 content in rat choroid plexus was determined to be 3.7 fmol/μg protein, whereas the LRP2 content was below the detection limit (<0.2 fmol/μg protein). Conditionally, immortalized rat choroid plexus epithelial cells exhibited predominant apical-to-basal and apical-to-cell transport of [(125) I]hAβ(1-40). These results indicated that hAβ(1-40) is actively eliminated from CSF and this process is at least partly mediated by LRP1 expressed at choroid plexus epithelial cells, which therefore play a role in determining CSF concentrations of hAβ(1-40).
authors.affiliation: Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Masachika
authors.initials: M
authors.lastname: Fujiyoshi
authors.forename: Masanori
authors.initials: M
authors.lastname: Tachikawa
authors.forename: Sumio
authors.initials: S
authors.lastname: Ohtsuki
authors.forename: Shingo
authors.initials: S
authors.lastname: Ito
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchida
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Akanuma
authors.forename: Junichi
authors.initials: J
authors.lastname: Kamiie
authors.forename: Tadafumi
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Hosoya
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Terasaki
mesh_terms: D000465:Algorithms; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D000818:Animals; D001693:Biological Transport, Active / Q000502:physiology; D001812:Blood-Brain Barrier / Q000502:physiology*; D002460:Cell Line; D002831:Choroid Plexus / Q000166:cytology; D007276:Injections, Intraventricular; D007700:Kinetics; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000097:blood / Q000378:metabolism*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000097:blood / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016229:Amyloid beta-Peptides; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)