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

Shingo Ito, Kohta Matsumiya, Sumio Ohtsuki, Junichi Kamiie, Tetsuya Terasaki

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1770-1777
Number of pages8
JournalJournal of Cerebral Blood Flow and Metabolism
Volume33
Issue number11
DOIs
Publication statusPublished - 2013 Nov 1

Keywords

  • Alzheimer's disease
  • Aβ-degrading enzyme
  • amyloid-β peptide
  • blood-brain barrier
  • efflux transport

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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