Montine K S, Olson S J, Amarnath V, Whetsell W O, Graham D G, Montine T J
Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Am J Pathol. 1997 Feb;150(2):437-43.
Cumulative oxidative damage, including lipid peroxidation, is a central component of cellular aging and is thought to play a role in the pathogenesis of late-onset Alzheimer's disease (AD). Lipid peroxidation produces several cytotoxic aldehydes, one of the most potent being 4-hydroxy-2-nonenal (HNE). We have shown previously that HNE is a potent neurotoxin that covalently modifies and cross-links neuronal cytoskeletal protein in neuroglial cultures, suggesting that HNE may contribute to the pathogenesis of AD. In addition to aging, inheritance of the epsilon 4 allele of APOE is the other major risk factor for development of late-onset AD; however, the mechanisms through which aging and apolipoprotein E isoforms may collaborate in the onset or progression of AD are not known. We tested the hypothesis that HNE may yield a particular type of protein modification, pyrrole adduction, and that this may contribute to the pathogenesis of AD. Our data demonstrated that HNE formed pyrrole adducts with protein. Polyclonal antiserum was raised that specifically recognized HNE pyrrole adducts, and immunohistochemical analysis was performed on hippocampus and temporal cortex of 10 patients with histologically verified AD. Pyramidal neuron cytoplasm was immunoreactive in 4 of 4 APOE4 homozygotes, 2 of 3 APOE3/4 heterozygotes, and none of 3 APOE3 homozygotes (P < 0.05). The pattern of staining was highly suggestive of neurofibrillary tangles as the primary immunoreactive structure. These data suggest that differences in neuronal protein modification by HNE may account in part for the APOE-associated stratification of risk for late-onset AD.
包括脂质过氧化在内的累积性氧化损伤是细胞衰老的核心组成部分，并且被认为在晚发性阿尔茨海默病（AD）的发病机制中发挥作用。脂质过氧化产生几种细胞毒性醛类，其中最具毒性的一种是4-羟基-2-壬烯醛（HNE）。我们之前已经表明，HNE是一种强效神经毒素，它能在神经胶质细胞培养物中与神经元细胞骨架蛋白发生共价修饰和交联，这表明HNE可能促成了AD的发病机制。除衰老外，APOE的ε4等位基因遗传是晚发性AD发生的另一个主要风险因素；然而，衰老和载脂蛋白E亚型在AD发病或进展过程中可能协同作用的机制尚不清楚。我们检验了这样一个假设，即HNE可能产生一种特定类型的蛋白质修饰——吡咯加合物，并且这可能促成AD的发病机制。我们的数据表明，HNE与蛋白质形成了吡咯加合物。制备了能特异性识别HNE吡咯加合物的多克隆抗血清，并对10例经组织学证实为AD的患者的海马体和颞叶皮质进行了免疫组织化学分析。在4例APOE4纯合子中有4例、3例APOE3/4杂合子中有2例的锥体神经元细胞质呈免疫反应性，而3例APOE3纯合子中无一例呈免疫反应性（P<0.05）。染色模式强烈提示神经原纤维缠结是主要的免疫反应性结构。这些数据表明，HNE对神经元蛋白质修饰的差异可能部分解释了与APOE相关的晚发性AD风险分层。
