G protein βγ 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 co-segregate 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 G₀, which consists of Gα₀, and Gβγ 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 Gα₀, or Gα(i) induced little apoptosis. Apoptosis by V642I APP was antagonized by the overexpression of the carboxy-terminal amino acids 495-689 of the β-adrenergic receptor kinase-l, which blocks the specific functions of Gβγ. Co-transfection of Gβ2γ2 cDNAs, but not that of other Gβxγz (x = 1-3; z = 2, 3), induced DNA fragmentation in a manner sensitive to bcl-2. These data implicate Gβγ as a cell death mediator for the FAD-associated mutant of APP.