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This Article Summary Full Text Full Text (PDF) All Versions of this Article: fj.05-4891fjev1 fj.05-4891fjev2 20/8/1191    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Szegedi, V. Articles by Penke, B. Search for Related Content PubMed PubMed Citation Articles by Szegedi, V. Articles by Penke, B.

Endomorphin-2, an endogenous tetrapeptide, protects against Aß1–42 in vitro and in vivo

Viktor Szegedi^*,1, 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 Zarándi^*, Dénes Budai^||, József Toldi and Botond Penke^*

^* Department of Medical Chemistry, University of Szeged;

Department of Comparative Physiology, University of Szeged;

Department of Analytical and Inorganic Chemistry, University of Szeged;

Institute of Biophysics, Biological Research Centre, Hungarian Academy of Sciences;

^|| Department of Biology, Juhász Gyula College, University of Szeged; and

^¶ Institute of Biochemistry, Biological Research Center of the Hungarian Academy of Sciences, Szeged, Hungary

¹Correspondence: Department of Medical Chemistry, University of Szeged, Dóm Square 8, Szeged 6720, Hungary. E-mail: szegv{at}mdche.szote.u-szeged.hu

ABSTRACT

The underlying cause of Alzheimer’s disease (AD) is thought to be the ß-amyloid aggregates formed mainly by Aß1–42 peptide. Protective pentapeptides [e.g., Leu-Pro-Phe-Phe-Asp (LPFFD)] have been shown to prevent neuronal toxicity of Aß1–42 by arresting and reversing fibril formation. Here we report that an endogenous tetrapeptide, endomorphin-2 (End-2, amino acid sequence: YPFF), defends against Aß1–42 induced neuromodulatory effects at the cellular level. Although End-2 does not interfere with the kinetics of Aß fibrillogenesis according to transmission electron microscopic studies and quasielastic light scattering measurements, it binds to Aß1–42 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 Aß1–42 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 Aß1–42. Studies using [D-Ala (2) , N-Me-Phe (4) , Gly (5) -ol]-enkephalin (DAMGO), a µ-opioid receptor agonist, show that the protective effects of the tetrapeptide are not µ-receptor modulated. The endogenous tetrapeptide End-2 may serve as a lead compound for the drug development in the treatment of AD.—Szegedi, V., Juhász, G., Rózsa, E., Juhász-Vedres, G., Datki, Z., Fülöp, L., Bozsó, Z., Lakatos, A., Laczkó, I., Farkas, T., Kis, Z., Tóth, G., Soós, K., Zarándi, M., Budai, D., Toldi, J., Penke, B. Endomorphin-2, an endogenous tetrapeptide, protects against Aß1–42 in vitro and in vivo.