Copper-dependent inhibition of human cytochrome c oxidase by a dimeric conformer of amyloid-beta1-42.
In studies of Alzheimer's disease pathogenesis there is an increasing focus on mechanisms of intracellular amyloid-beta (Abeta) generation and toxicity. Here we investigated the inhibitory potential of the 42 amino acid Abeta peptide (Abeta1-42) on activity of electron transport chain enzyme complexes in human mitochondria. We found that synthetic Abeta1-42 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 Abeta1-42 solution. Maximal COX inhibition occurred when using Abeta1-42 solutions aged for 3-6 h at 30 degrees C. The level of Abeta1-42-mediated COX inhibition increased with aging time up to approximately 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 Abeta as the only Abeta 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 Abeta immunoreactivity within the brain mitochondria fraction. Our data indicate that endogenous Abeta is associated with brain mitochondria and that Abeta1-42, possibly in its dimeric conformation, is a potent inhibitor of COX, but only when in the presence of Cu2+. We conclude that Cu2+-dependent Abeta-mediated inhibition of COX may be an important contributor to the neurodegeneration process in Alzheimer's disease.
Crouch
Peter J
PJ
Centre for Neuroscience, The University of Melbourne, Victoria 3010, Australia.
Blake
Rachel
R
Duce
James A
JA
Ciccotosto
Giuseppe D
GD
Li
Qiao-Xin
QX
Barnham
Kevin J
KJ
Curtain
Cyril C
CC
Cherny
Robert A
RA
Cappai
Roberto
R
Dyrks
Thomas
T
Masters
Colin L
CL
Trounce
Ian A
IA
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D003300:Copper / Q000502:physiology*; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism; D046912:Multiprotein Complexes; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors
D016229:Amyloid beta-Peptides; D046912:Multiprotein Complexes; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D003300:Copper; D003576:Electron Transport Complex IV