Effects of beta-amyloid-(25-35) peptides on radioligand binding to excitatory amino acid receptors and voltage-dependent calcium channels: Evidence for a selective affinity for the glutamate and glycine recognition sites of the NMDA receptor

The neurotoxic fragment corresponding to residues 25-35 of the beta-amyloid (A beta) peptide [A beta-(25-35)] has been shown to exert effects on (+)-[H-3]5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclo-hepten-5,10-imine maleate ([H-3]MK-801) binding to the cation channel of the N -methyl-D-aspartate (NMDA) receptor. In the present study, we investigated whether the amidated and carboxylic acid C-terminated forms of A beta-(25-35) [A beta-(25-35-NH2) and A beta-(25-35-COOH), respectively] exert effects on other excitatory amino acid receptor and cation channel types in rat cortical membranes. Both A beta-(25-35-NH2) and A beta-(25-35-COOH) gave statistically significant dose-dependent inhibitions of [H-3]glutamate and [H-3]glycine binding to the agonist recognition sites of the NMDA receptor. Ten mu M A beta-(25-35-NH2) and A beta-(25-35-COOH) gave 25% and 20% inhibitions of [H-3]glutamate binding and 75% and 70% inhibitions of [H-3]glycine binding, respectively. A beta-(25-35-NH2), but not A beta-(25-35-COOH), gave a small (ca. 17% at 10 mu M) statistically significant increase of [H-3]amino-3-hydroxy-5-methylisoxazole-4-propionate ([H-3]AMPA) binding, [H-3]kainate binding was not significantly affected by either peptide. Similarly, neither peptide affected either the maximal level or EC50 value for calcium stimulation of [H-3]nitrendipine binding. It is concluded that A beta-(25-35) shows slight affinity for the agonist recognition sites of the NMDA receptor, but not for other excitatory amino acid receptor types or for L-type voltage-dependent calcium channels.