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Endomorphin‐2, an endogenous tetrapeptide, protects against Aβ1‐42 in vitro and in vivo

2006; Wiley; Volume: 20; Issue: 8 Linguagem: Inglês

10.1096/fj.05-4891fje

1530-6860

Viktor Szegedi, Gábor Juhász, Éva Rózsa, Gabriella Juhász-Vedres, Zsolt Datki, Lívia Fülöp, Zsolt Bozsó, Andrea Lakatos, Ilona Laczkó, T. Farkas, Zsolt Kis, Géza Tóth, Katalin Soós, Márta Zaráindi, Dénes Budai, József Toldi, Botond Penke, Viktor Szegedi, Gábor Juhász, Éva Rózsa, Gabriella Juhász-Vedres, Zsolt Datki, Lívia Fülöp, Zsolt Bozsó, Andrea Lakatos, Ilona Laczkó, Tamás Farkas, Zsolt Kis, Géza Tóth, Katalin Soós, Márta Zaráindi, Dénes Budai, József Toldi, Botond Penke,

Supramolecular Self-Assembly in Materials

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.