The cell-selective neurotoxicity of the Alzheimer's Aβ peptide is determined by surface phosphatidylserine and cytosolic ATP levels.: Membrane binding is required for Aβ toxicity

Measurement of A beta toxicity of cells in culture exposes a subpopulation of cells with resistance to A beta, even at high concentrations and after long periods of treatment. The cell-selective toxicity of A beta resembles the selective damage observed in cells of specific regions of the Alzheimer's disease ( AD) brain and suggests that there must be particular characteristics or stages of these cells that make them exceptionally sensitive or resistant to the effect of A beta. Using flow cytometry and cell sorting, we efficiently separated and analyzed the A beta-sensitive and the A beta- resistant subpopulations within a variety of neuronal cell lines (PC12, GT1-7) and primary cultured neurons (hippocampal, cortex). We found that this distinctive sensitivity to A beta was essentially associated with cell membrane A beta binding. This selective A beta binding was correlated to distinctive cell characteristics, such as cell membrane exposure of the apoptotic signal molecule phosphatidyl serine, larger cell size, the G(1) cell cycle stage, and a lower than normal cytosolic ATP level. The response to A beta by the cells with high A beta binding affinity was characterized by a larger calcium response and increased mortality, lactate dehydrogenase release, caspase activation, and DNA fragmentation. The distinctive sensitivity or resistance to A beta of the different subpopulations was maintained even after multiple cell divisions. We believe that these distinctive cell characteristics are the determining factors for the selective attack of A beta on cells in culture and in the AD brain.