BETA A4-EVOKED DEGENERATION OF DIFFERENTIATED SH-SY5Y HUMAN NEUROBLASTOMA-CELLS/

beta/A4 peptides are known to induce neurodegeneration in cultures of rat brain cells and rat neural cell lines (Yankner et al: Science 250: 279-282, 1990; Behl et al: Biochem Biophys Res Commun 186:944-950, 199 2). The current data show that these peptides induce similar neurodege neration in SH-SY5Y neuroblastoma cells, extending characterization of beta/A4 toxicity to a human nerve cell line. Humam SH-SY5Y cells resp ond to aggregated beta/A4 with changes in cell shape, membrane blebbin g, antigenic modification, loss of attachment to the substrate, and ce ll death, beta/A4 peptides require aggregation for maximum toxic effec ts, as cellular degeneration is evoked by aggregated beta/A4 1-42 and 4-41 cysteine but not by monomeric beta/A4 1-40, Aged (pre-aggregated) beta/A4 1-40 also evoked neurodegeneration. Antigenic changes compris e upregulation of Alzheimer's-type tau epitopes, recognized by the PHF -1 and Alz-50 monoclonals. These particular changes in tau support the connectivity between this in vitro model and mechanisms leading to ne urodegeneration in Alzheimer's disease. A significant feature of the S H-SY5Y response is that cells must be differentiated before they becom e sensitive to the degeneration evoked by beta/A4. Signaling pathways leading to beta/A4-evoked neurodegeneration thus are under experimenta l control, becoming complete only when proliferating cells withdraw fr om the cell cycle and develop a postmitotic phenotype. (C) 1991 Wiley- Liss, Inc.