Endomorphin-2, an endogenous tetrapeptide, protects against A beta 1-42 in vitro and in vivo

Szegedi, Viktor and Juhász, Gábor and Rózsa, Éva and Juhász-Vedres, Gabriella and Datki, Zsolt and Fülöp, Lívia and Bozsó, Zsolt and Lakatos, Andrea and Laczkó, Ilona and Farkas, Tamás and Kis, Zsolt and Tóth, Géza and Soós, Katalin and Zarándi, Márta and Budai, Dénes and Toldi, József and Penke, Botond (2006) Endomorphin-2, an endogenous tetrapeptide, protects against A beta 1-42 in vitro and in vivo. FASEB Journal, 20 (8). pp. 1191-1193. ISSN 0892-6638 (print), 1530-6860 (online)

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Abstract

The underlying cause of Alzheimer's disease ( AD) is thought to be the beta-amyloid aggregates formed mainly by A beta 1-42 peptide. Protective pentapeptides [ e. g., Leu-Pro-Phe-Phe-Asp (LPFFD)] have been shown to prevent neuronal toxicity of A beta 1-42 by arresting and reversing fibril formation. Here we report that an endogenous tetrapeptide, endomorphin-2 (End-2, amino acid sequence: YPFF), defends against A beta 1-42 induced neuromodulatory effects at the cellular level. Although End-2 does not interfere with the kinetics of A beta fibrillogenesis according to transmission electron microscopic studies and quasielastic light scattering measurements, it binds to A beta 1-42 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 A beta 1-42 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 responseenhancing effect of A beta 1-42. 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.

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