Amyloid beta-peptide (A beta P) potentiates a nimodipine-sensitive L-type barium conductance in N1E-115 neuroblastoma cells.
The neurodegenerative pathology observed in Alzheimer's Disease (AD) has been partially attributed to the neurotoxic effects of the amyloid beta-peptide (A beta P), although the mechanisms underlying this neurotoxicity are unknown. Since A beta P is capable of forming cation channels in lipid bilayers, it is possible that the neurotoxic effects on neurons may be mediated by a cation flux. We have used patch-clamp recording techniques to study the effects of A beta P on cation currents in differentiated mouse N1E-115 neuroblastoma cells. In whole-cell recordings, incubation of cells with A beta P for 24 h significantly increased the median peak inward current from -201.8 pA to -352.0 pA, and shifted the voltage at peak current (Vpeak) and that of current activation (Vact) towards more positive potentials. For untreated cells, median Vpeak was 1.7 mV and Vact was -28.9 mV, vs. 10.5 mV and -24.7 mV in A beta P-treated cells. Incubation with the reverse sequence A beta P(40-1) or A beta P(25-35) did not produce significant changes in the amplitude or kinetic behavior of the inward current. At the single channel level, A beta P added to the pipette increased the open probability of cation-conducting ion channels. As determined by cell viability counts, both A beta P(1-40) and the A beta P(25-35) fragment had neurotoxic effects; within 24 h, addition of A beta P reduced the number of viable cells by more than 50%. It is suggested that the neurotoxic effects of A beta P may be mediated by its ability to form cation channels de novo and/or alter the activity of cation channels already present in the cell membrane.
Davidson
R M
RM
Department of Periodontology, University of Connecticut Health Center, Farmington 06030.
Shajenko
L
L
Donta
T S
TS
D000544:Alzheimer Disease / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000494:pharmacology*; D000818:Animals; D017609:Barium Compounds / Q000494:pharmacology; D002460:Cell Line; D002712:Chlorides / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D009447:Neuroblastoma; D009553:Nimodipine / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D016564:Amyloid beta-Protein Precursor; D017609:Barium Compounds; D002712:Chlorides; D007473:Ion Channels; C024986:barium chloride; D009553:Nimodipine