期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 104, 期 35, 页码 14163-14168出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0705738104
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资金
- NCI NIH HHS [R01 CA085700-07, R01 CA085700] Funding Source: Medline
- NEI NIH HHS [R01 EY010804-13, R01 EY010804] Funding Source: Medline
- NINDS NIH HHS [R01-NS41777, R01 NS041777-07, R01 NS041777, R01 NS041777-08] Funding Source: Medline
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 farnesyltransf erase 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.
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