Endomorphin-2, an endogenous tetrapeptide, protects against Abeta1-42 in vitro and in vivo

• Published in: The FASEB journal 2006-06, Vol.20 (8), p.1191
• Main Authors: Szegedi, Viktor, Juhász, Gábor, Rózsa, Eva, Juhász-Vedres, Gabriella, Datki, Zsolt, Fülöp, Lívia, Bozsó, Zsolt, Lakatos, Andrea, Laczkó, Ilona, Farkas, Tamás, Kis, Zsolt, Tóth, Géza, Soós, Katalin, Zarándi, Márta, Budai, Dénes, Toldi, József, Penke, Botond
• Format: Article
• Language: English
• Subjects: Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - ultrastructure; Animals; Cell Line, Tumor; Cell Survival - drug effects; Cells, Cultured; Circular Dichroism; Enkephalin, Ala-MePhe-Gly- - pharmacology; Evoked Potentials; Excitatory Postsynaptic Potentials - drug effects; Iontophoresis; Light; Microscopy, Electron, Transmission; N-Methylaspartate - metabolism; Neurons - drug effects; Neurons - physiology; Neuroprotective Agents - metabolism; Neuroprotective Agents - pharmacology; Oligopeptides - metabolism; Oligopeptides - pharmacology; Peptide Fragments - antagonists & inhibitors; Peptide Fragments - chemistry; Peptide Fragments - ultrastructure; Radioligand Assay; Rats; Rats, Wistar; Scattering, Radiation
• ISSN: 1530-6860
• DOI: 10.1096/fj.05-4891fje

The underlying cause of Alzheimer's disease (AD) is thought to be the beta-amyloid aggregates formed mainly by Abeta1-42 peptide. Protective pentapeptides [e.g., Leu-Pro-Phe-Phe-Asp (LPFFD)] have been shown to prevent neuronal toxicity of Abeta1-42 by arresting and reversing fibril formation. Here we report that an endogenous tetrapeptide, endomorphin-2 (End-2, amino acid sequence: YPFF), defends against Abeta1-42 induced neuromodulatory effects at the cellular level. Although End-2 does not interfere with the kinetics of Abeta fibrillogenesis according to transmission electron microscopic studies and quasielastic light scattering measurements, it binds to Abeta1-42 during aggregation, as revealed by tritium-labeled End-2 binding assay and circular dichroism measurements. The tetrapeptide attenuates the inhibitory effect on cellular redox activity of Abeta1-42 in a dose-dependent manner, as measured by 3-(4,5-dimethylthiazolyl-2)-2,-5-diphenyltetrazolium bromide (MTT) assay. In vitro and in vivo electrophysiological experiments show that End-2 also protects against the field excitatory postsynaptic potential attenuating and the NMDA-evoked response-enhancing effect of Abeta1-42. Studies using [D-Ala (2), N-Me-Phe (4), Gly (5)-ol]-enkephalin (DAMGO), a mu-opioid receptor agonist, show that the protective effects of the tetrapeptide are not mu-receptor modulated. The endogenous tetrapeptide End-2 may serve as a lead compound for the drug development in the treatment of AD.