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

PJ Crouch, R Blake, JA Duce… - Journal of …, 2005 - Soc Neuroscience
PJ Crouch, R Blake, JA Duce, GD Ciccotosto, QX Li, KJ Barnham, CC Curtain, RA Cherny…
Journal of Neuroscience, 2005Soc Neuroscience
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 …
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 then declined progressively with continued aging to 48 h. Photo-induced cross-linking of unmodified proteins followed by SDS-PAGE analysis revealed dimeric Aβ as the only Aβ species to provide significant temporal correlation with the observed COX inhibition. Analysis of brain and liver from an Alzheimer's model mouse (Tg2576) revealed abundant Aβ immunoreactivity within the brain mitochondria fraction. Our data indicate that endogenous Aβ is associated with brain mitochondria and that Aβ1-42, possibly in its dimeric conformation, is a potent inhibitor of COX, but only when in the presence of Cu2+. We conclude that Cu2+-dependent Aβ-mediated inhibition of COX may be an important contributor to the neurodegeneration process in Alzheimer's disease.
Soc Neuroscience