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 Q(10) 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.

译文

与膜相关的氧化应激与阿尔茨海默氏病 (AD) 中发生的突触功能障碍和神经元变性有关,但其潜在机制尚不清楚。质膜氧化还原系统 (PMRS) 的酶为能量代谢和抗氧化剂的回收提供电子。在这里,我们显示了3xTgAD小鼠 (AD的动物模型) 的海马和大脑皮质质膜中几种PMRS酶的活性选择性降低。我们的结果表明PMRS酶活性降低与辅酶q (10) 水平降低和氧化应激标记物水平升高有关。过表达PMRS酶 (NQO1或细胞色素b5还原酶) 的神经元对淀粉样 β 肽 (a β) 的抵抗力增强。A β 是否以及在何种程度上是3xtgad小鼠中PMRS酶受损的原因尚不清楚。因为这些小鼠也表达突变的tau和presenilin-1,所以一个或多个pmr可能受到这些突变的不利影响。尽管如此,我们的细胞培养研究结果清楚地表明,神经元暴露于Aβ1-42足以损害PMRS酶。AD动物模型中PMRS的损害以及PMRS酶活性保护神经元免受a β 毒性的能力,表明增强PMRS功能是保护神经元免受AD和相关疾病氧化损伤的一种新方法。

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