Central beta-amyloid peptide-induced peripheral interleukin-6 responses inmice

beta -Amyloid peptides (A betas) share with lipopolysaccharide, a potent pr o-inflammatory agent, the property of stimulating glial cells or macrophage s to induce various inflammatory mediators. We recently reported that centr al administration of lipopolysaccharide induces peripheral interleukin-6 re sponses via both the central and peripheral norepinephrine system. In this study, the effect of intracerebroventricular injection of various synthetic Aps on plasma interleukin-6 levels was examined in mice. A beta (1-42) dos e-dependently increased plasma interleukin-6 levels: 'aged' A beta (1-42) w as more effective than fresh, whereas A beta (42-1) had no effect. 'Aged' A beta (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 A beta (1-4 2)-induced brain interleukin-6, tumor necrosis factor-alpha and interleukin -1 beta level, which was 4, 4 and 24 h, respectively. Among various periphe ral organs, A beta (1-42) (205 pmol/ mouse i.c.v.), significantly increased interleukin-6 mRNA expression in lymph nodes and liver. A beta (1-42) (205 pmol/mouse i.c.v.) significantly increased norepinephrine turnover in both hypothalamus and spleen. Either central or peripheral norepinephrine deple tion effectively inhibited the A beta (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)-adre nergic antagonist), but not with betaxolol (pr-adrenergic antagonist), inhi bited A beta (1-42)-induced plasma interleukin-6 levels. These results demo nstrate that centrally administered A beta (1-42) effectively induces the s ystemic interleukin-6 response which is mediated, in part, by central A bet a (1-42)-induced activation of the central and the peripheral norepinephrin e systems. Keywords: Alzheimer's disease, g-hydroxydopamine, intracerebrove ntricular injection, norepinephrine, sympathetic nervous system.