Central β‐amyloid peptide‐induced peripheral interleukin‐6 responses in mice

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Abstract
β-Amyloid peptides (Aβs) 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 Aβs on plasma interleukin-6 levels was examined in mice. Aβ1−42 dose-dependently increased plasma interleukin-6 levels: ‘aged’ Aβ1−42 was more effective than fresh, whereas Aβ42−1 had no effect. ‘Aged’ Aβ1−42 (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 Aβ1−42-induced brain interleukin-6, tumor necrosis factor-α and interleukin-1β levels, which was 4, 4 and 24 h, respectively. Among various peripheral organs, Aβ1−42 (205 pmol/mouse i.c.v.) significantly increased interleukin-6 mRNA expression in lymph nodes and liver. Aβ1−42 (205 pmol/mouse i.c.v.) significantly increased norepinephrine turnover in both hypothalamus and spleen. Either central or peripheral norepinephrine depletion effectively inhibited the Aβ1−42-induced peripheral interleukin-6 response. Pretreatment with prazosin (α1-adrenergic antagonist), yohimbine (α2-adrenergic antagonist), and ICI-118,551 (β2-adrenergic antagonist), but not with betaxolol (β1-adrenergic antagonist), inhibited Aβ1−42-induced plasma interleukin-6 levels. These results demonstrate that centrally administered Aβ1−42 effectively induces the systemic interleukin-6 response which is mediated, in part, by central Aβ1−42-induced activation of the central and the peripheral norepinephrine systems.