Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease
Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease
复制标题
DOI：
10.1073/pnas.0705738104
复制
发表时间：
2007-08-28
影响因子：
11.1
通讯作者：
Moraes, Carlos T.
中科院分区：
文献类型：
--
作者：
Fukui, Hirokazu;Diaz, Francisca;Moraes, Carlos T.
线粒体细胞色素c氧化酶（考克斯）的缺陷与阿尔茨海默病相关，其中β-淀粉样蛋白的年龄依赖性积累在突触功能障碍和神经变性中起重要作用。为了测试年龄依赖性线粒体呼吸功能下降的可能性，特别是考克斯活性，可能参与β-淀粉样蛋白的形成和积累，我们产生了表达突变型淀粉样蛋白前体蛋白和突变型早老素1的小鼠在神经元特异性COX-缺乏的背景。通过Cre-loxP系统产生神经元特异性COX缺陷型小鼠，其中通过CamKII α启动子驱动的Cre重组酶缺失COX 10基因。COX 10是参与血红素a生物合成的法尼基转移酶，血红素a是考克斯组装和功能所需的。这些KO小鼠在大脑皮层和海马中显示出年龄依赖性的考克斯缺陷。令人惊讶的是，COX 10基因敲除小鼠的大脑中的淀粉样蛋白斑块明显少于COX-competent转基因小鼠。KO小鼠中淀粉样蛋白斑块的减少伴随着A β 42水平、β-分泌酶活性和氧化损伤的降低。同样，从具有部分考克斯活性的细胞中产生的活性氧也没有升高。总的来说，我们的研究结果表明，与以前的模型相反，神经元考克斯的缺陷不会增加氧化损伤，也不会导致淀粉样蛋白前体蛋白片段的形成。
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.