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.