Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease

@article{citeulike:1583274, abstract = {Edited by L. L. Iversen, University of Oxford, Oxford, United Kingdom, and approved July 20, 2007 (received for review June 19, 2007)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 CamKII{alpha} 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 A{beta}42 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. 10.1073/pnas.0705738104}, author = {Fukui, Hirokazu and Diaz, Francisca and Garcia, Sofia and Moraes, Carlos T. }, citeulike-article-id = {1583274}, doi = {http://dx.doi.org/10.1073/pnas.0705738104}, journal = {PNAS}, keywords = {alzheimer, ox\_stress}, month = {August}, pages = {0705738104+}, posted-at = {2007-08-22 16:18:09}, priority = {2}, title = {Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease}, url = {http://dx.doi.org/10.1073/pnas.0705738104}, year = {2007} }

TY - JOUR ID - citeulike:1583274 L3 - citeulike-article-id:1583274 TI - Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease JF - PNAS SP - 0705738104 N2 - Edited by L. L. Iversen, University of Oxford, Oxford, United Kingdom, and approved July 20, 2007 (received for review June 19, 2007)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 CamKII{alpha} 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 A{beta}42 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. 10.1073/pnas.0705738104 KW - alzheimer KW - ox_stress AU - Fukui, Hirokazu AU - Diaz, Francisca AU - Garcia, Sofia AU - Moraes, Carlos PY - 2007/08/21/ UR - http://dx.doi.org/10.1073/pnas.0705738104 ER -