We have demonstrated that normal betaAPP695 behave as a signaling receptor and indicated that point mutations at V642 create autoactive betaAPP in signal transduction. Cellular expression of those familial Alzheimer's disease-associated mutants causes neuronal cells to undergo apoptotic death; and procedures inhibiting the signal of normal betaAPP block the mutant-induced apoptosis. We have also shown that the mutant-induced death is mediated by intracellular G protein activity but not by secretion of Abeta peptides. Accordingly, the mutant-induced death requires a cytoplasmic domain but not the 41st and 42nd residues of the Abeta region. These studies provide a novel insight that betaAPP may play a normal role as a death receptor and that Alzheimer's disease-relevant abnormality occurred in this function may lead neurons to suicidal degeneration.