Eliminating membrane depolarization caused by the Alzheimer peptide Abeta(1-42, aggr.).
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.
Blanchard
Barbara J
BJ
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Stockwell
Brent R
BR
Ingram
Vernon M
VM
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D018118:Chloride Channels / Q000737:chemistry; D018491:Dopamine Agonists / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008564:Membrane Potentials; D008954:Models, Biological; D016716:PC12 Cells; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000378:metabolism; D013050:Spectrometry, Fluorescence
D016229:Amyloid beta-Peptides; D018118:Chloride Channels; D018491:Dopamine Agonists; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D011505:Protein-Tyrosine Kinases; D018091:Receptors, AMPA; D017366:Serotonin Receptor Agonists; C075222:amyloid beta-protein (1-42)