Cytotoxicity mediated by conditional expression of a carboxyl-terminal derivative of the β-amyloid precursor protein

The β amyloid peptide which accumulates within the brains of patients with Alzheimer's disease (AD) is proteolytically derived from a precursor protein (βPP). We established and characterized four stably transformed human neuroblastoma cell lines which conditionally expressed a partial βPP fusion protein (amino-17 residues + carboxyl-99 residues; SβC). Conditional expression of SβC was achieved using a tetracycline-responsive promoter system. Expression of this fusion protein in one of the cell lines resulted in pronounced cytotoxicity. Addition of n6,O2′-dibutyryl adenosine 3′,5′-cyclic monophosphate and/or fetal bovine serum to the culture medium of this cell line further elevated the level of SβC expression and enhanced the associated cytotoxicity. Conditioned medium, acquired from cells expressing SβC, was not cytotoxic. These findings suggest that modulation of βPP expression and/or metabolism can have cytotoxic consequences. This is the first report of cytotoxic effects mediated by conditional expression of a βPP derivative. This immortal cell line provides a unique opportunity to screen for complementary DNAs which suppress this toxicity. Such cDNAs could help elucidate the processes underlying SβC mediated cytotoxicity which in turn could further our understanding of the pathogenesis of AD and could also provide additional candidate genes for various forms of familial AD.