Crouch, Peter J.;
Blake, Rachel;
Duce, James A.;
Ciccotosto, Giuseppe D.;
Li, Qiao-Xin;
Barnham, Kevin J.;
Curtain, Cyril C.;
Cherny, Robert A.;
Cappai, Roberto;
Dyrks, Thomas;
Masters, Colin L.;
Trounce, Ian A.
Copper-Dependent Inhibition of Human CytochromecOxidase by a Dimeric Conformer of Amyloid-β1-42
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Medientyp:
E-Artikel
Titel:
Copper-Dependent Inhibition of Human CytochromecOxidase by a Dimeric Conformer of Amyloid-β1-42
Beteiligte:
Crouch, Peter J.;
Blake, Rachel;
Duce, James A.;
Ciccotosto, Giuseppe D.;
Li, Qiao-Xin;
Barnham, Kevin J.;
Curtain, Cyril C.;
Cherny, Robert A.;
Cappai, Roberto;
Dyrks, Thomas;
Masters, Colin L.;
Trounce, Ian A.
Beschreibung:
<jats:p>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 (Aβ<jats:sub>1-42</jats:sub>) on activity of electron transport chain enzyme complexes in human mitochondria. We found that synthetic Aβ<jats:sub>1-42</jats:sub>specifically inhibited the terminal complex cytochrome<jats:italic>c</jats:italic>oxidase (COX) in a dose-dependent manner that was dependent on the presence of Cu<jats:sup>2+</jats:sup>and specific “aging” of the Aβ<jats:sub>1-42</jats:sub>solution. Maximal COX inhibition occurred when using Aβ<jats:sub>1-42</jats:sub>solutions aged for 3-6 h at 30°C. The level of Aβ<jats:sub>1-42</jats:sub>-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 Aβ<jats:sub>1-42</jats:sub>, possibly in its dimeric conformation, is a potent inhibitor of COX, but only when in the presence of Cu<jats:sup>2+</jats:sup>. We conclude that Cu<jats:sup>2+</jats:sup>-dependent Aβ-mediated inhibition of COX may be an important contributor to the neurodegeneration process in Alzheimer's disease.</jats:p>