Involvement of insulin-degrading enzyme in insulin-and atrial natriuretic peptide-sensitive internalization of amyloid-β peptide in mouse brain capillary endothelial cells

Shingo Ito, Sumio Ohtsuki, Sho Murata, Yuki Katsukura, Hiroya Suzuki, Miho Funaki, Masanori Tachikawa, Tetsuya Terasaki

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

Cerebral clearance of amyloid-β peptide (Aβ), which is implicated in Alzheimer's disease, involves elimination across the blood-brain barrier (BBB), and we previously showed that an insulin-sensitive process is involved in the case of Aβ1-40. The purpose of this study was to clarify the molecular mechanism of the insulin-sensitive Aβ1-40 elimination across mouse BBB. An in vivo cerebral microinjection study demonstrated that [125I]hAβ1-40 elimination from mouse brain was inhibited by human natriuretic peptide (hANP), and [ 125I]hANP elimination was inhibited by hAβ1-40, suggesting that hAβ1-40 and hANP share a common elimination process. Internalization of [125I]hAβ1-40 into cultured mouse brain capillary endothelial cells (TM-BBB4) was significantly inhibited by either insulin, hANP, other natriuretic peptides or insulin-degrading enzyme (IDE) inhibitors, but was not inhibited by phosphoramidon or thiorphan. Although we have reported the involvement of natriuretic peptide receptor C (Npr-C) in hANP internalization, cells stably expressing Npr-C internalized [125I]hANP but not [ 125I]hAβ1-40, suggesting that there is no direct interaction between Npr-C and hAβ1-40. IDE was detected in plasma membrane of TM-BBB4 cells, and internalization of [125I] hAβ1-40 by TM-BBB4 cells was reduced by IDE-targeted siRNAs. We conclude that elimination of hAβ1-40 from mouse brain across the BBB involves an insulin-and ANP-sensitive process, mediated by IDE expressed in brain capillary endothelial cells.

Original languageEnglish
Pages (from-to)185-200
Number of pages16
JournalJournal of Alzheimer's Disease
Volume38
Issue number1
DOIs
Publication statusPublished - 2014

Keywords

  • Alzheimer's disease
  • amyloid-β peptide
  • atrial natriuretic peptide
  • blood-brain barrier
  • brain capillary endothelial cells
  • insulin-degrading enzyme

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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