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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.

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