Endomorphin-2, an endogenous tetrapeptide, protects against Abeta1-42 in vitro and in vivo.
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.
Szegedi
Viktor
V
Department of Medical Chemistry, University of Szeged, Dóm Square 8, Szeged 6720, Hungary. szegv@mdche.szote.u-szeged.hu
Juhász
Gábor
G
Rózsa
Eva
E
Juhász-Vedres
Gabriella
G
Datki
Zsolt
Z
Fülöp
Lívia
L
Bozsó
Zsolt
Z
Lakatos
Andrea
A
Laczkó
Ilona
I
Farkas
Tamás
T
Kis
Zsolt
Z
Tóth
Géza
G
Soós
Katalin
K
Zarándi
Márta
M
Budai
Dénes
D
Toldi
József
J
Penke
Botond
B
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
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