The current study determined the ability of a p75(NTR) antagonistic cyclic peptide to rescue cells from beta amyloid (A beta) (1-40)-induced death. p75(NTR)-, p140(trkA)-NIH-3T3 cells or E17 foetal rat cortical neurones were incubated with I-125-NGF or I-125-A beta (1-40) and increasing concentrations of the cyclic peptide (CATDIKGAEC). Peptide ability to displace I-125-NGF or I-125-A beta (1-40) binding was determined. Duplicate cultures were preincubated with CATDIKGAEC (250 nM) or diluent and then stimulated with A beta (1-40). Peptide ability to displace A beta (1-40) binding, interfere with A beta (1-40)-induced signalling and rescue cells from A beta-mediated toxicity was determined by immunoprecipitation and autoradiography, Northern blotting, JNK activation, MTT and trypan blue assays. The peptide inhibited NGF and A beta (1-40) binding to p75(NTR), but not to p140(trkA). A beta (1-40) induced c-jun transcription (57.3% +/- 0.07%) in diluent-treated p75(NTR)-cells, but not in cells preincubated with the cyclic peptide. Also, at 250 nM, the peptide reduced A beta (1-40)-induced phsophorylation of JNK by 71.8% +/- 0.03% and protected neurones against A beta-induced toxicity as determined by: trypan blue exclusion assay (53% +/- 11% trypan blue-positive cells in diluent pretreated cultures vs. 28% +/- 5% in cyclic peptide-pretreated cultures); MTT assay (0.09 +/- 0.03 units in diluent-pretreated cells vs. 0.12 +/- 0.004 units in cyclic peptide-pretreated cells); and visualization of representative microscopic fields. Our data suggest that a cyclic peptide homologous to amino acids 28-36 of NGF known to mediate binding to p75(NTR) can interfere with A beta (1-40) signalling and rescue neurones from A beta (1-40)-induced toxicity.