Mechanism of membrane depolarization caused by the Alzheimer Abeta1-42 peptide.
We report a novel observation that the neurotoxic Alzheimer peptide Abeta1-42, when pre-incubated, causes a dramatic and lasting membrane depolarization in differentiated human hNT neuronal cells and in rodent PC12 cells in a concentration-dependent manner. This phenomenon involves activation of the metabotropic glutamate receptor, mGluR(1). Abeta-induced membrane depolarization in PC12 cells is sensitive to mGluR(1) antagonists and to pertussis and cholera toxins, indicating the involvement of particular G-proteins. The effect is different from the known ability of aggregated Abeta1-42 to cause a calcium influx. Since mGluR(1) agonists mimic the Abeta effect, we deduce that in this cell system glutamate can control the membrane potential and thereby the excitability of its target neurons. We propose that Abeta-induced membrane depolarization described here leads in Alzheimer's disease to hyperexcitability of affected neurons and is a crucially important molecular mechanism for beta-amyloid toxicity and cognitive dysfunction in the disease.
Blanchard
Barbara J
BJ
Department of Biology, Massachusetts Institute of Technology, 31 Ames Street, Cambridge, MA 02139, USA.
Thomas
Veena L
VL
Ingram
Vernon M
VM
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002138:Calibration; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D002772:Cholera Toxin / Q000494:pharmacology; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D007700:Kinetics; D009474:Neurons / Q000378:metabolism; D016716:PC12 Cells; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051381:Rats; D018091:Receptors, AMPA / Q000737:chemistry; D013997:Time Factors; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D002118:Calcium; D002772:Cholera Toxin; D019204:GTP-Binding Proteins; D007473:Ion Channels; D010446:Peptide Fragments; D018091:Receptors, AMPA; D010566:Virulence Factors, Bordetella; C075222:amyloid beta-protein (1-42)