Short fragments and fragment analogues of beta-amyloid 1-42 peptide (Abeta1-42) display a protective effect against Abeta-mediated neurotoxicity. After consideration of our earlier results with in vitro bioassay of synthetic Abeta-recognition peptides and toxic fibrillar amyloids, five pentapeptides were selected as putative neuroprotective agents: Phe-Arg-His-Asp-Ser amide (Abeta4-8) and Gly-Arg-His-Asp-Ser amide (an analogue of Abeta4-8), Leu-Pro-Tyr-Phe-Asp amide (an analogue of Abeta17-21), Arg-Ile-Ile-Gly-Leu amide (an analogue of Abeta30-34), and Arg-Val-Val-Ile-Ala amide (an analogue of Abeta38-42). In vitro electrophysiological experiments on rat brain slices demonstrated that four of these peptides counteracted with the field excitatory postsynaptic potential-attenuating effect of Abeta1-42; only Arg-Val-Val-Ile-Ala amide proved inactive. In in vivo experiments using extracellular single-unit recordings combined with iontophoresis, all these pentapeptides except Arg-Val-Val-Ile-Ala amide protected neurons from the NMDA response-enhancing effect of Abeta1-42 in the hippocampal CA1 region. These results suggest that Abeta recognition sequences may serve as leads for the design of novel neuroprotective compounds.