Pentapeptides derived from Abeta 1-42 protect neurons from the modulatory effect of Abeta fibrils--an in vitro and in vivo electrophysiological study.
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.
Szegedi
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Department of Medical Chemistry, University of Szeged, Dóm tér 8, Szeged H-6720, Hungary. szegv@yahoo.com
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D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000682:Amyloid / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000502:physiology* / Q000648:ultrastructure; D000818:Animals; D004594:Electrophysiology; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D009842:Oligopeptides / Q000302:isolation & purification / Q000502:physiology*; D010446:Peptide Fragments / Q000502:physiology* / Q000648:ultrastructure; D051381:Rats; D017208:Rats, Wistar
D000682:Amyloid; D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D009842:Oligopeptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016202:N-Methylaspartate