EXPRESSION OF V642 APP MUTANT CAUSES CELLULAR APOPTOSIS AS ALZHEIMER TRAIT-LINKED PHENOTYPE

APP is a transmembrane precursor of beta-amyloid. In dominantly inheri ted familial Alzheimer's disease (FAD), point mutations V642I, V642F a nd V642G have been discovered in APP(695). Here we show that expressio n of these mutants (FAD-APPs) causes a clone of COS cells to undergo a poptosis associated with DNA fragmentation, Apoptosis by the three FAD -APPs was the highest among all possible V642 mutants; normal APP(695) had no effect on apoptosis, suggesting that apoptosis by APP mutants in this system is phenotypically linked to the FAD trait. FAD-APP-indu ced apoptosis was sensitive to bcl-2 and most probably mediated by het eromeric G proteins. This study presents a model system allowing analy sis of the mechanism for FAD-APP-induced cytotoxicity.