Aggregates of a beta-amyloid peptide are required to induce calcium currents in neuron-like human teratocarcinoma cells: relation to Alzheimer's disease.
We report that human hNT cells display neuron-like calcium channel activation. Patch-clamp experiments show that exposure of hNT cells to the Alzheimer-related amyloid peptide beta AP(25-35) induces large and irreversible inward calcium currents at -80 mV in whole cell mode, with a linear current-voltage relationship. This behavior is suggestive of ionophore formation. An analogous peptide with scrambled sequence has no effect. These ionophore effects by the beta AP(25-35) peptide, the first report in a human cell-line, are very rapid effects. The currents are large and stable, and are blocked by Al3+ but not by Cd2+. Filtration removes a peptide aggregate from the amyloid peptide beta AP(25-35) solution and thereby abolishes the inward current. The residual soluble peptide has no effect. These data suggest that the initial step of the neurotoxic effect of beta AP(25-35) may be due to the insertion of the aggregated peptide into the cellular membrane as a Ca2(+)-carrying ionophore. The relevance of calcium-mediated cell death, especially in Alzheimer's disease, is discussed.
Sanderson
K L
KL
Department of Biology, Massachusetts Institute of Technology, Cambridge 01239, USA.
Butler
L
L
Ingram
V M
VM
D000535:Aluminum / Q000494:pharmacology; D000544:Alzheimer Disease / Q000503:physiopathology*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D004553:Electric Conductivity; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D007476:Ionophores / Q000378:metabolism; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000502:physiology; D018408:Patch-Clamp Techniques; D018243:Teratocarcinoma; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000502:physiology
D016229:Amyloid beta-Peptides; D007476:Ionophores; D013757:Tetraethylammonium Compounds; D013779:Tetrodotoxin; D019789:Tetraethylammonium; D000535:Aluminum; D002118:Calcium