G protein beta gamma complex-mediated apoptosis by familial Alzheimer's disease mutant of APP
Open Access
- 15 August 1997
- journal article
- research article
- Published by Springer Nature in The EMBO Journal
- Vol. 16 (16) , 4897-4907
- https://doi.org/10.1093/emboj/16.16.4897
Abstract
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 Go, which consists of Gαo 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 Gαo or Gαi 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‐1, 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.Keywords
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