Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease.
Defects in the mitochondrial cytochrome c oxidase (COX) have been associated with Alzheimer's Disease, in which the age-dependent accumulation of beta-amyloid plays an important role in synaptic dysfunction and neurodegeneration. To test the possibility that age-dependent decline in the mitochondrial respiratory function, especially COX activity, may participate in the formation and accumulation of beta-amyloid, we generated mice expressing mutant amyloid precursor protein and mutant presenilin 1 in a neuron-specific COX-deficient background. A neuron-specific COX-deficient mouse was generated by the Cre-loxP system, in which the COX10 gene was deleted by a CamKIIalpha promoter-driven Cre-recombinase. COX10 is a farnesyltransferase involved in the biosynthesis of heme a, required for COX assembly and function. These KO mice showed an age-dependent COX deficiency in the cerebral cortex and hippocampus. Surprisingly, COX10 KO mice exhibited significantly fewer amyloid plaques in their brains compared with the COX-competent transgenic mice. This reduction in amyloid plaques in the KO mouse was accompanied by a reduction in Abeta42 level, beta-secretase activity, and oxidative damage. Likewise, production of reactive oxygen species from cells with partial COX activity was not elevated. Collectively, our results suggest that, contrary to previous models, a defect in neuronal COX does not increase oxidative damage nor predispose for the formation of amyloidgenic amyloid precursor protein fragments.
Fukui
Hirokazu
H
Neuroscience Program and Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Diaz
Francisca
F
Garcia
Sofia
S
Moraes
Carlos T
CT
D000544:Alzheimer Disease / Q000235:genetics*; D000682:Amyloid / Q000096:biosynthesis*; D000818:Animals; D002950:Citrate (si)-Synthase / Q000378:metabolism; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology; D009474:Neurons / Q000201:enzymology*; D018384:Oxidative Stress; D010101:Oxygen Consumption; D010545:Peroxides / Q000378:metabolism
D000682:Amyloid; D010545:Peroxides; D003576:Electron Transport Complex IV; D002950:Citrate (si)-Synthase
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