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

Abstract

Defects in the mitochondrial cytochrome c oxidase (COX) have been associated with Alzheimer's Disease, in which the agedependent accumulation of ␤-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 ␤-amyloid, we generated mice expressing mutant amyloid precursor protein and mutant presenilin 1 in a neuron-specific COX-deficient background. A neuron-specific COXdeficient mouse was generated by the Cre-loxP system, in which the COX10 gene was deleted by a CamKII␣ promoter-driven Crerecombinase. 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␤42 level, ␤-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. mitochondria ͉ oxidative phosphorylation ͉ neurodegeneration A lzheimer's disease (AD) is the most prevalent age-related neurodegenerative disease, characterized by progressive brain atrophy/neuronal death that results in cognitive and memory impairment. Starting from the identification of genes responsible for familial AD, which is now known to constitute only Ͻ5% of total AD incidence, an ''amyloid hypothesis'' has been built up during the past few decades, and an enormous effort has been devoted to understand the toxic mechanism of ␤-amyloid (A␤), which forms extracellular amyloid plaques and is generated by a successive proteolytic cleavage of amyloid precursor protein (APP) by ␤-secretase and a ␥-secretase complex containing presenilins (1). Although it is not clear to what extent different A␤ species (soluble oligomers, insoluble aggregates, extracellular species, or intracellular species) contribute to neurodegeneration in vivo, recent studies demonstrated the toxicity of diverse A␤ species in vitro, in situ, and in vivo, confirming the importance of age-dependent A␤ accumulation in AD pathogenesis (2-5).Recently, age-dependent accumulation of mutations in mitochondrial DNA (mtDNA) and resulting increase in oxidative stress and impairment in mitochondrial respiratory chain, especially complex IV or cytochrome c oxidase (COX), gained attention as potential factors that could participate in the onset of sporadic AD (6). A number of studies reported a reduction in COX activity and an increase in oxidative stress in brain tissues and plate...

The mitochondrial impairment, oxidative stress and neurodegeneration connection: reality or just an attractive hypothesis?

“…To assess whether a genetically induced complex IV deficiency affects oxidative stress and production/accumulation of Aβ, we have first generated neuron-specific conditional COX10 knockout mice and then crossed them with a mouse model of AD to generate complex IVdeficient AD mice (COXd/AD mice) [53]. Contrary to our expectation, brains of COXd/AD mice exhibited less amyloid plaque and reduced Aβ deposition, as compared to AD mice.…”

“…These studies consistently demonstrated a strong correlation between oxidative stress and accumulation of Aβ with the possible involvement of an APP-processing enzyme, β-secretase [53][54][55][56][57]. A recent report using heterozygous Mn-SOD knockout mice also showed that oxidative stress modulates hyperphosphorylation of tau, which leads to the formation of neurofibrillary tangles [58].…”

“…We concluded that an isolated complex IV defect does not contribute to oxidative stress and AD pathology, and that the increased oxidative damage found in patients and animal models of AD is a consequence of Aβ accumulation. Furthermore, we showed that partial inhibition of complex IV in fibroblasts does not affect ROS production [53]. Nevertheless, the effect of partial complex IV inhibition on ROS production in postmitotic neurons or adult CNS in vivo and its potential contribution to AD remain to be investigated.…”

“…To address the contribution of oxidative stress to the development of pathological features of AD, different groups employed various pharmacological and genetic approaches to modulate oxidative stress in mouse models of AD expressing mutant forms of human APP [53] (and references therein). These studies consistently demonstrated a strong correlation between oxidative stress and accumulation of Aβ with the possible involvement of an APP-processing enzyme, β-secretase [53][54][55][56][57].…”

The pathophysiology of mitochondrial disease as modeled in the mouse

“…The COX assembly protein, Cox10, was selectively inactivated in mouse muscle, neurons, and liver (Diaz et al 2005(Diaz et al , 2008Fukui et al 2007). Muscle-specific Cox10-depleted animals develop a regressive myopathy and weakness, starting the age of 3 mo and leading to death at between 4 and 10 mo.…”