G protein beta gamma complex-mediated apoptosis by familial Alzheimer's disease mutant of APP

In familial Alzheimer's disease (FAD), three missense mutations, V642I, V642F and V642G, that cosegregate with the disease phenotype have been discovered in the 695 amino acid form of the amyloid precursor protein APP, Expression of these mutants causes a COS cell NK1 clone to undergo pertussis toxin-sensitive apoptosis in an FAD trait-linked manner by activating the G protein G(0), which consists of G alpha(0) and G beta gamma subunits, We investigated which subunit was responsible for the induction of apoptosis by V642I APP in NK1 cells, In the same system, expression of mutationally activated G alpha(0), or G alpha(i) induced little apoptosis, Apoptosis by V642I APP was antagonized by the overexpression of the carboxy-terminal amino acids 495-689 of the beta-adrenergic receptor kinase-1, which blocks the specific functions of G beta gamma. Co-transfection of G beta 2 gamma 2 cDNAs, but not that of other G beta x gamma z (x = 1-3; z = 2, 3), induced DNA fragmentation in a manner sensitive to bcl-2, These data implicate G beta gamma as a cell death mediator for the FAD-associated mutant of APP.