Eliminating membrane depolarization caused by the Alzheimer peptide Abeta(1-42, aggr.)

Biochem Biophys Res Commun. 2002 May 17;293(4):1204-8. doi: 10.1016/S0006-291X(02)00290-5.

Abstract

A high-throughput screen found compounds that eliminate the dramatic membrane depolarization caused by the aggregated Alzheimer Abeta1-42 peptide, which activates mGluR1 receptors. The library was composed of known biologically active compounds; the cell-based assay measured the changes of membrane potential with a slow-acting voltage-sensitive dye. We found 10 potentially useful compounds, some of which reduce the Abeta-induced membrane depolarization up to 96%. Interestingly, the active compounds include specific tyrosine kinase inhibitors and inhibitors of certain chloride channels. We deduce that mGluR1 receptors, activated by Abeta1-42 or otherwise, can control the membrane potential via downstream activation of certain tyrosine kinases and certain ion channels. Dopaminergic and serotonergic agonists that emerged from the screen presumably compensate for the Abeta-induced membrane depolarization by themselves causing a hyperpolarization. The hit compounds, whose pharmacokinetics are known, show promise for the restoration of cognitive function in the treatment of early and mid-stage Alzheimer's disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism
  • Amyloid beta-Peptides / chemistry*
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Cell Membrane / metabolism
  • Chloride Channels / chemistry
  • Dopamine Agonists / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Membrane Potentials
  • Models, Biological
  • PC12 Cells
  • Peptide Fragments / chemistry*
  • Peptide Fragments / metabolism*
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Rats
  • Receptors, AMPA / metabolism*
  • Serotonin Receptor Agonists / metabolism
  • Spectrometry, Fluorescence

Substances

  • Amyloid beta-Peptides
  • Chloride Channels
  • Dopamine Agonists
  • Enzyme Inhibitors
  • Peptide Fragments
  • Receptors, AMPA
  • Serotonin Receptor Agonists
  • amyloid beta-protein (1-42)
  • Protein-Tyrosine Kinases
  • glutamate receptor ionotropic, AMPA 1