G-PROTEIN BETA-GAMMA COMPLEX-MEDIATED APOPTOSIS BY FAMILIAL ALZHEIMERS-DISEASE MUTANT OF APP

In familial Alzheimer's disease (FAD), three missense mutations, V642I , V642F and V642G, that cosegregate with the disease phenotype have be en discovered in the 695 amino acid form of the amyloid precursor prot ein APP, Expression of these mutants causes a COS cell NK1 clone to un dergo pertussis toxin-sensitive apoptosis in an FAD trait-linked manne r by activating the G protein G(0), which consists of G alpha(0) and G beta gamma subunits, We investigated which subunit was responsible fo r the induction of apoptosis by V642I APP in NK1 cells, In the same sy stem, expression of mutationally activated G alpha(0), or G alpha(i) i nduced little apoptosis, Apoptosis by V642I APP was antagonized by the overexpression of the carboxy-terminal amino acids 495-689 of the bet a-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 fragmentat ion 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.