Inheritance of apolipoprotein E4 (APOE4) is a major risk factor for development of Alzheimer's disease (AD). This lipoprotein, in contrast to apoE2, has arginine residues at positions 112 and 158 in place of cysteines in the latter isoform. In apoE3, the Cys at residue 158 is replaced by an arginine residue. This differential amino acid composition of the three genotypes of APOE have profound influence on the structure, binding properties, and multiple functions of this lipoprotein. Moreover, AD brain is under a high degree of oxidative stress, including that associated with amyloid β-peptide (Aβ) oligomers. Lipid peroxidation produces the highly reactive and neurotoxic molecule, 4-hydroxynonenal (HNE) that forms covalent bonds with cysteine residues (Cys) [as well as with Lys and His residues]. Covalently modified Cys significantly alter structure and function of modified proteins. HNE bound to Cys residue(s) on apoE2 and apoE3 lessens the chance of HNE damage other proteins. apoE4, lacking Cys residues, is unable to scavenge HNE, permitting this latter neurotoxic molecule to lead to oxidative modification of neuronal proteins and eventual cell death. We posit that this lack of HNE scavenging activity in apoE4 significantly contributes to the association of APOE4 inheritance and increased risk of developing AD. Apoe knock-out mice provide insights into the role of this lipoprotein in oxidative stress. Targeted replacement mice in which the mouse gene of Apoe is separately replaced by the human APOE2, APOE3, or APOE4 genes, while keeping the mouse promoter assures the correct location and amount of the human protein isoform. Human APOE targeted replacement mice have been used to investigate the notion that oxidative damage to and death of neurons in AD and its earlier stages is related to APOE genotype. This current paper reviews the intersection of human APOE genotype, oxidative stress, and diminished function of this lipoprotein as a major contributing risk factor for development of AD. Discussion of potential therapeutic strategies to mitigate against the elevated risk of developing AD with inheritance of the APOE4 allele also is presented.

中文翻译：

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与阿尔茨海默氏病有关的脑中载脂蛋白E和氧化应激。

载脂蛋白E4（APOE4）的遗传是阿尔茨海默氏病（AD）发展的主要危险因素。与apoE2相反，该脂蛋白在位置112和158处具有精氨酸残基，以取代后者的同工型中的半胱氨酸。在apoE3中，残基158的Cys被精氨酸残基代替。三种基因型的APOE的这种不同的氨基酸组成对该脂蛋白的结构，结合特性和多功能具有深远的影响。此外，AD脑处于高度氧化应激，包括与淀粉样β肽（Aβ）低聚物相关的氧化应激。脂质过氧化产生高反应性和神经毒性分子4-羟基壬烯醛（HNE），它与半胱氨酸残基（Cys）[以及Lys和His残基]形成共价键。共价修饰的Cys会显着改变修饰蛋白的结构和功能。与apoE2和apoE3上的Cys残基结合的HNE减少了HNE破坏其他蛋白质的机会。缺少Cys残基的apoE4无法清除HNE，从而使后者的神经毒性分子导致神经元蛋白质的氧化修饰并最终导致细胞死亡。我们认为，在apoE4中缺乏HNE清除活性，极大地促进了APOE4遗传的关联并增加了发展AD的风险。Apoe基因敲除小鼠提供了这种脂蛋白在氧化应激中的作用的见解。有针对性的替代小鼠，其中Apoe的小鼠基因被人类APOE2，APOE3或APOE4基因分别替代，同时保留了小鼠启动子，确保了人类蛋白同工型的正确位置和数量。以人为APOE的替代小鼠已用于研究AD及其早期阶段神经元的氧化损伤和死亡与APOE基因型有关的观念。本文综述了人类APOE基因型，氧化应激和这种脂蛋白功能减弱的交叉点，脂蛋白是导致AD发展的主要危险因素。还介绍了潜在的治疗策略，以减轻通过APOE4等位基因遗传而发展为AD的风险。并降低了这种脂蛋白的功能，这是导致AD发展的主要危险因素。还介绍了潜在的治疗策略，以减轻通过APOE4等位基因遗传而发展为AD的风险。并降低了这种脂蛋白的功能，这是导致AD发展的主要危险因素。还介绍了潜在的治疗策略，以减轻通过APOE4等位基因遗传而发展为AD的风险。