Endomorphin-2, an endogenous tetrapeptide, protects against Abeta1-42 in vitro and in vivo

FASEB J. 2006 Jun;20(8):1191-3. doi: 10.1096/fj.05-4891fje. Epub 2006 Apr 24.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / antagonists & inhibitors*
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / ultrastructure
  • Animals
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cells, Cultured
  • Circular Dichroism
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology
  • Evoked Potentials
  • Excitatory Postsynaptic Potentials / drug effects
  • Iontophoresis
  • Light
  • Microscopy, Electron, Transmission
  • N-Methylaspartate / metabolism
  • Neurons / drug effects
  • Neurons / physiology
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / pharmacology*
  • Oligopeptides / metabolism
  • Oligopeptides / pharmacology*
  • Peptide Fragments / antagonists & inhibitors*
  • Peptide Fragments / chemistry
  • Peptide Fragments / ultrastructure
  • Radioligand Assay
  • Rats
  • Rats, Wistar
  • Scattering, Radiation


  • Amyloid beta-Peptides
  • Neuroprotective Agents
  • Oligopeptides
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • endomorphin 2
  • N-Methylaspartate