NEURODEGENERATIVE MECHANISMS IN ALZHEIMER-DISEASE - A ROLE FOR OXIDATIVE DAMAGE IN AMYLOID-BETA PROTEIN PRECURSOR-MEDIATED CELL-DEATH

We have established a stably transformed human neuroblastoma cell line (MC65) that conditionally expresses a C-terminal derivative of the am yloid beta protein precursor (beta PP) termed S beta C (a fusion prote in composed of the amino-17 and carboxyl-99 residues of beta PP). Cond itional expression of S beta C (mediated by the withdrawal of tetracyc line from the culture medium) induces pronounced nuclear DNA fragmenta tion and cytotoxicity in this cell line. These effects are enhanced by hyperoxygen and suppressed by hypooxygen and antioxidants. This cell line is relatively insensitive to the extracellular application of amy loid beta(25-35), and coculture experiments suggest that this cytotoxi city is mediated by an intracellular process. These findings suggest t hat the overexpression of the C-terminal domain of beta PP can disrupt normal cellular processes in these cells in such a way as to induce a directed (deoxyribonuclease-mediated) mechanism of cell death. This p rocess appears to be modulated and/or mediated by a reactive oxygen sp ecie(s) (ROS). Consistent with a role for ROS in the process of S beta C-mediated toxicity, we have found that the MC65 cell line is hyperse nsitive to oxidative stress and that it is this sensitivity that appea rs (at least in part) to underlie its susceptibility to S beta C.