Copper-Dependent Inhibition of Human Cytochrome c Oxidase by a Dimeric Conformer of Amyloid-β1-42

摘要: In studies of Alzheimer9s disease pathogenesis there is an increasing focus on mechanisms intracellular amyloid-β (Aβ) generation and toxicity. Here we investigated the inhibitory potential 42 amino acid Aβ peptide (Aβ 1-42 ) activity electron transport chain enzyme complexes in human mitochondria. We found that synthetic specifically inhibited terminal complex cytochrome c oxidase (COX) a dose-dependent manner was dependent presence Cu 2+ specific “aging” solution. Maximal COX inhibition occurred when using solutions aged for 3-6 h at 30°C. The level -mediated increased with aging time up to ∼6 then declined progressively continued 48 h. Photo-induced cross-linking unmodified proteins followed by SDS-PAGE analysis revealed dimeric as only species provide significant temporal correlation observed inhibition. Analysis brain liver from model mouse (Tg2576) abundant immunoreactivity within mitochondria fraction. Our data indicate endogenous associated , possibly its conformation, potent inhibitor COX, but . conclude -dependent Aβ-mediated may be important contributor neurodegeneration process disease.