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The Journal of Neuroscience, January 19, 2005, 25(3):672-679; doi:10.1523/JNEUROSCI.4276-04.2005

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Neurobiology of Disease
Copper-Dependent Inhibition of Human Cytochrome c Oxidase by a Dimeric Conformer of Amyloid-_1-42

Peter J. Crouch,¹ Rachel Blake,¹ James A. Duce,¹ Giuseppe D. Ciccotosto,^2,3 Qiao-Xin Li,^2,3 Kevin J. Barnham,^2,3 Cyril C. Curtain,^2,3,4 Robert A. Cherny,^2,3 Roberto Cappai,^2,3 Thomas Dyrks,⁵ Colin L. Masters,^1,2,3 and Ian A. Trounce¹

¹Centre for Neuroscience and ²Department of Pathology, The University of Melbourne, Victoria 3010, Australia, ³Mental Health Research Institute of Victoria, Parkville, Victoria 3052, Australia, ⁴School of Physics and Materials Engineering, Monash University, Clayton, Victoria 3168, Australia, and ⁵Diagnostics and Radiopharmacy Research, Schering AG, D-13342 Berlin, Germany

In studies of Alzheimer's disease pathogenesis there is an increasing focus on mechanisms of intracellular amyloid- (A) generation and toxicity. Here we investigated the inhibitory potential of the 42 amino acid A peptide (A_1-42) on activity of electron transport chain enzyme complexes in human mitochondria. We found that synthetic A_1-42 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 A_1-42 solution. Maximal COX inhibition occurred when using A_1-42 solutions aged for 3-6 h at 30°C. The level of A_1-42-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 A as the only A 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 A immunoreactivity within the brain mitochondria fraction. Our data indicate that endogenous A is associated with brain mitochondria and that A_1-42, possibly in its dimeric conformation, is a potent inhibitor of COX, but only when in the presence of Cu²⁺. We conclude that Cu²⁺-dependent A-mediated inhibition of COX may be an important contributor to the neurodegeneration process in Alzheimer's disease.

Key words: Alzheimer's disease; amyloid-; cytochrome oxidase; copper; mitochondria; Tg2576

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Received Oct 14, 2004; revised November 19, 2004; accepted November 25, 2004.

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