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 Aβ toxicity of cells in culture exposes a subpopulation of cells with resistance to Aβ, even at high concentrations and after long periods of treatment. The cell-selective toxicity of Aβ 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 Aβ. Using flow cytometry and cell sorting, we efficiently separated and analyzed the Aβ-sensitive and the Aβ-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 Aβ was essentially associated with cell membrane Aβ binding. This selective Aβ binding was correlated to distinctive cell characteristics, such as cell membrane exposure of the apoptotic signal molecule phosphatidyl serine, larger cell size, the G1 cell cycle stage, and a lower than normal cytosolic ATP level. The response to Aβ by the cells with high Aβ 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 Aβ 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 Aβ on cells in culture and in the AD brain.