Central beta-amyloid peptide-induced peripheral interleukin-6 responses in mice

J Neurochem. 2001 Mar;76(5):1326-35. doi: 10.1046/j.1471-4159.2001.00121.x.

Abstract

beta-Amyloid peptides (Abetas) share with lipopolysaccharide, a potent pro-inflammatory agent, the property of stimulating glial cells or macrophages to induce various inflammatory mediators. We recently reported that central administration of lipopolysaccharide induces peripheral interleukin-6 responses via both the central and peripheral norepinephrine system. In this study, the effect of intracerebroventricular injection of various synthetic Abetas on plasma interleukin-6 levels was examined in mice. Abeta(1-42) dose-dependently increased plasma interleukin-6 levels: 'aged' Abeta(1-42) was more effective than fresh, whereas Abeta(42-1) had no effect. 'Aged' Abeta(1-42) (205 pmol/mouse i.c.v.)-induced plasma interleukin-6 peaked at 2 h post injection, which is earlier than the peak time of the Abeta(1-42)-induced brain interleukin-6, tumor necrosis factor-alpha and interleukin-1beta levels, which was 4, 4 and 24 h, respectively. Among various peripheral organs, Abeta(1-42) (205 pmol/mouse i.c.v.) significantly increased interleukin-6 mRNA expression in lymph nodes and liver. Abeta(1-42) (205 pmol/mouse i.c.v.) significantly increased norepinephrine turnover in both hypothalamus and spleen. Either central or peripheral norepinephrine depletion effectively inhibited the Abeta(1-42)-induced peripheral interleukin-6 response. Pretreatment with prazosin (alpha(1)-adrenergic antagonist), yohimbine (alpha(2)-adrenergic antagonist), and ICI-118,551 (beta(2)-adrenergic antagonist), but not with betaxolol (beta(1)-adrenergic antagonist), inhibited Abeta(1-42)-induced plasma interleukin-6 levels. These results demonstrate that centrally administered Abeta(1-42) effectively induces the systemic interleukin-6 response which is mediated, in part, by central Abeta(1-42)-induced activation of the central and the peripheral norepinephrine systems.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / administration & dosage
  • Amyloid beta-Peptides / pharmacology*
  • Animals
  • Brain / drug effects
  • Brain / immunology
  • Brain / physiology*
  • Cerebral Ventricles / drug effects
  • Cerebral Ventricles / physiology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / immunology
  • Injections, Intraventricular
  • Interleukin-1 / genetics
  • Interleukin-6 / blood*
  • Interleukin-6 / genetics*
  • Kinetics
  • Male
  • Mice
  • Mice, Inbred ICR
  • Norepinephrine / metabolism*
  • Oxidopamine / pharmacology
  • Peptide Fragments / administration & dosage
  • Peptide Fragments / pharmacology*
  • RNA, Messenger / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Structure-Activity Relationship
  • Time Factors
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / immunology
  • Tumor Necrosis Factor-alpha / genetics

Substances

  • Amyloid beta-Peptides
  • Interleukin-1
  • Interleukin-6
  • Peptide Fragments
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Oxidopamine
  • Norepinephrine