title: Endomorphin-2, an endogenous tetrapeptide, protects against Abeta1-42 in vitro and in vivo.
abstract: 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.
authors.affiliation: Department of Medical Chemistry, University of Szeged, Dóm Square 8, Szeged 6720, Hungary. szegv@mdche.szote.u-szeged.hu
authors.forename: Viktor
authors.initials: V
authors.lastname: Szegedi
authors.forename: Gábor
authors.initials: G
authors.lastname: Juhász
authors.forename: Eva
authors.initials: E
authors.lastname: Rózsa
authors.forename: Gabriella
authors.initials: G
authors.lastname: Juhász-Vedres
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Datki
authors.forename: Lívia
authors.initials: L
authors.lastname: Fülöp
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Bozsó
authors.forename: Andrea
authors.initials: A
authors.lastname: Lakatos
authors.forename: Ilona
authors.initials: I
authors.lastname: Laczkó
authors.forename: Tamás
authors.initials: T
authors.lastname: Farkas
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Kis
authors.forename: Géza
authors.initials: G
authors.lastname: Tóth
authors.forename: Katalin
authors.initials: K
authors.lastname: Soós
authors.forename: Márta
authors.initials: M
authors.lastname: Zarándi
authors.forename: Dénes
authors.initials: D
authors.lastname: Budai
authors.forename: József
authors.initials: J
authors.lastname: Toldi
authors.forename: Botond
authors.initials: B
authors.lastname: Penke
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000648:ultrastructure; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002942:Circular Dichroism; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D005071:Evoked Potentials; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D007478:Iontophoresis; D008027:Light; D046529:Microscopy, Electron, Transmission; D016202:N-Methylaspartate / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000648:ultrastructure; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D012542:Scattering, Radiation
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D009842:Oligopeptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C105294:endomorphin 2; D016202:N-Methylaspartate