A NEW PARADIGM FOR NEUROTOXICITY BY FAD MUTANTS OF BETA-APP - A SIGNALING ABNORMALITY

We have demonstrated that normal beta APP(695) behave as a signaling r eceptor and indicated that point mutations at V642 create autoactive b eta APP in signal transduction. Cellular expression of those familial Alzheimer's disease-associated mutants causes neuronal cells to underg o apoptotic death; and procedures inhibiting the signal of normal beta APP block the mutant-induced apoptosis. We have also shown that the m utant-induced death is mediated by intracellular G protein activity bu t not by secretion of A beta peptides. Accordingly, the mutant-induced death requires a cytoplasmic domain but not the 41st and 42nd residue s of the A beta region. These studies provide a novel insight that bet a APP may play a normal role as a death receptor and that Alzheimer's disease-relevant abnormality occurred in this function may lead neuron s to suicidal degeneration. (C) 1998 Elsevier Science Inc.