Short fragments and fragment analogues of beta-amyloid 1–42 peptide (Aβ1–42) display a protective effect against Aβ-mediated neurotoxicity. After consideration of our earlier results with in vitro bioassay of synthetic Aβ-recognition peptides and toxic fibrillar amyloids, five pentapeptides were selected as putative neuroprotective agents: Phe-Arg-His-Asp-Ser amide (Aβ4–8) and Gly-Arg-His-Asp-Ser amide (an analogue of Aβ4–8), Leu-Pro-Tyr-Phe-Asp amide (an analogue of Aβ17–21), Arg-Ile-Ile-Gly-Leu amide (an analogue of Aβ30–34), and Arg-Val-Val-Ile-Ala amide (an analogue of Aβ38–42). In vitro electrophysiological experiments on rat brain slices demonstrated that four of these peptides counteracted with the field excitatory postsynaptic potential-attenuating effect of Aβ1–42; 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 Aβ1–42 in the hippocampal CA1 region. These results suggest that Aβ recognition sequences may serve as leads for the design of novel neuroprotective compounds.