Membrane-associated oxidative stress has been implicated in the synaptic dysfunction and neuronal degeneration that occurs in Alzheimer's disease (AD), but the underlying mechanisms are unknown. Enzymes of the plasma membrane redox system (PMRS) provide electrons for energy metabolism and recycling of antioxidants. Here, we show that activities of several PMRS enzymes are selectively decreased in plasma membranes from the hippocampus and cerebral cortex of 3xTgAD mice, an animal model of AD. Our results that indicate the decreased PMRS enzyme activities are associated with decreased levels of coenzyme Q10 and increased levels of oxidative stress markers. Neurons overexpressing the PMRS enzymes (NQO1 or cytochrome b5 reductase) exhibit increased resistance to amyloid β-peptide (Aβ). If and to what extent Aβ is the cause of the impaired PMRS enzymes in the 3xTgAD mice is unknown. Because these mice also express mutant tau and presenilin-1, it is possible that one or more of the PMRS could be adversely affected by these mutations. Nevertheless, the results of our cell culture studies clearly show that exposure of neurons to Aβ1-42 is sufficient to impair PMRS enzymes. The impairment of the PMRS in an animal model of AD, and the ability of PMRS enzyme activities to protect neurons against Aβ-toxicity, suggest enhancement PMRS function as a novel approach for protecting neurons against oxidative damage in AD and related disorders.
Bibliographical noteFunding Information:
We thank Jose Manuel Villalba (Universidad de Córdoba, Spain) and David Ross (University of Colorado at Denver, USA) for providing antibodies against b5R and NQO1, respectively. We thank Alan Sartorelli (Yale University School of Medicine, USA) for giving pBE8 and pCB6 plasmid vectors. This research was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, USA, and by the Ewha Womans University Research Grant of 2007, South Korea.
- Alzheimer's disease
- Amyloid β-peptide
- Coenzyme Q
- Oxidative stress
- Plasma membrane redox system