The aim of this project is to widen the understanding of the neurotoxic mechanisms for amyloid precursor protein (APP) mutations related to early-onset familial Alzheimer’s disease (FAD). The study will be focused on the mechanisms of the V717 “London” FAD mutated APP, particularly of V717G APP, that might promote oxidative damage in plasma membranes, influence the signalling and energetic processes and other life-span features in nerve cells. Second, the project aims to understand the role of the methionine-722 in APP (Met722) oxidative state in the lipid-initiated oxidative cascades in cells expressing the V717G APP. In membranes of human temporal cortex V717G APP peptide fragment stimulated G-proteins by 6-fold, as compared to wild-type APP, presumably through an oxidative mechanism. This effect was completely abolished when the S atom in Met722 was substituted for a -CH2-group. Met35 within A??( 1-42) is suggested to interact with Gly33 and participate in formation of peroxyl free radicals. We hypothesise that Gly717 in APP similarly interacts with Met722. We will establish neuronal cell lines stably expressing V717G and V717G/M722A APP under the control of a tetracycline induced promotor. Third, the cells will be analyzed for neurotoxic mechanisms and apoptotic signals. This project would help us to explain the specific oxidative and neurotoxic mechanisms of London-mutated APP and help to develop new strategies for early treatment and prevention of various FAD phenotypes.