title: Contributions of degradation and brain-to-blood elimination across the blood-brain barrier to cerebral clearance of human amyloid-β peptide(1-40) in mouse brain.
abstract: The purpose of the present study was to estimate the relative contributions of degradation and brain-to-blood elimination processes to the clearance of microinjected human amyloid-β peptide(1-40) (hAβ(1-40)) from mouse cerebral cortex, using a solid-phase extraction method together with a newly developed ultraperformance liquid chromatography/tandem mass spectrometry (UPLC/MS/MS) quantitation method for intact hAβ(1-40). The clearance rate constant of hAβ(1-40) in mouse cerebral cortex was determined to be 3.21 × 10(-2)/min under conditions where the saturable brain-to-blood elimination process across the blood-brain barrier (BBB) was expected to be saturated. Thus, this clearance rate constant should mainly reflect degradation. The [(125)I]hAβ(1-40) elimination rate across the BBB under nonsaturating conditions was determined to be 1.48 × 10(-2)/min. Inhibition studies suggested that processes sensitive to insulin and phosphoramidon, which inhibit neprilysin, insulin-degrading enzyme, and endothelin-converting enzyme, are involved not only in degradation, but also in elimination of hAβ(1-40). In conclusion, our results suggest a dominant contribution of degradation to cerebral hAβ(1-40) clearance, and also indicate that a sequential process of degradation and elimination of degradation products is involved in cerebral hAβ(1-40) clearance.
authors: 1] Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan [2] SORST of the Japan Science and Technology Agency, Kawaguchi, Japan [3] Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors: Shingo
authors: S
authors: Ito
authors: Kohta
authors: K
authors: Matsumiya
authors: Sumio
authors: S
authors: Ohtsuki
authors: Junichi
authors: J
authors: Kamiie
authors: Tetsuya
authors: T
authors: Terasaki
mesh_terms: D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism*; D002853:Chromatography, Liquid; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008845:Microinjections; D010446:Peptide Fragments / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D052616:Solid Phase Extraction; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)
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