Copper-dependent inhibition of human cytochrome c oxidase by a dimeric conformer of amyloid-β1-42

Abstract

In studies of Alzheimer's disease pathogenesis there is an increasing focus on mechanisms of intracellular amyloid-β (Aβ) generation and toxicity. Here we investigated the inhibitory potential of the 42 amino acid Aβ peptide (Aβ1-42) on activity of electron transport chain enzyme complexes in human mitochondria. We found that synthetic Aβ1-42 specifically inhibited the terminal complex cytochrome c oxidase (COX) in a dose-dependent manner that was dependent on the presence of Cu2+ and specific "aging" of the Aβ1-42 solution. Maximal COX inhibition occurred when using Aβ1-42 solutions aged for 3-6 h at 30°C. The level of Aβ1-42- mediated COX inhibition increased with aging time up to ∼6 h and..