Münch G, Schinzel R, Loske C, Wong A, Durany N, Li J J, Vlassara H, Smith M A, Perry G, Riederer P
Physiological Chemistry, Biocenter, University of Würzburg, Federal Republic of Germany.
J Neural Transm (Vienna). 1998;105(4-5):439-61. doi: 10.1007/s007020050069.
Many approaches have been undertaken to understand Alzheimer's disease (AD) but the heterogeneity of the etiologic factors makes it difficult to define the clinically most important factor determining the onset and progression of the disease. However, there is increasing evidence that the previously so-called "secondary factors" such as a disturbed glucose metabolism, oxidative stress and formation of "advanced glycation endproducts" (AGEs) and their interaction in a vicious cycle are also important for the onset and progression of AD. AGEs are protein modifications that contribute to the formation of the histopathological and biochemical hallmarks of AD: amyloid plaques, neurofibrillary tangles and activated microglia. Oxidative modifications are formed by a complex cascade of dehydration, oxidation and cyclisation reactions, subsequent to a non-enzymatic reaction of sugars with amino groups of proteins. Accumulation of AGE-crosslinked proteins throughout life is a general phenomenon of ageing. However, AGEs are more than just markers of ageing since they can also exert adverse biologic effects on tissues and cells, including the activation of intracellular signal transduction pathways, leading to the upregulation of cytokine and free radical production (oxidative stress). Oxidative stress is involved in various divergent events leading to cell damage, including an increase in membrane rigidity, DNA strand breaks and an impairment in glucose uptake. In addition, other age-related metabolic changes such as depletion of antioxidants or decreased energy production by a disturbed glucose metabolism diminish the ability of the cell to cope with the effects of radical-induced membrane, protein and DNA damage. With our improving understanding of the molecular basis for the clinical symptoms of dementia, it is hoped that the elucidation of the etiologic causes, particularly the positive feedback loops involving radical damage and a reduced glucose metabolism, will help to develop novel "neuroprotective" treatment strategies able to interrupt this vicious cycle of oxidative stress and energy shortage in AD.
为了解阿尔茨海默病（AD），人们采取了多种方法，但病因因素的异质性使得难以确定决定该疾病发病和进展的临床上最重要的因素。然而，越来越多的证据表明，先前所谓的“次要因素”，如葡萄糖代谢紊乱、氧化应激和“晚期糖基化终产物”（AGEs）的形成及其在恶性循环中的相互作用，对AD的发病和进展也很重要。AGEs是蛋白质修饰产物，有助于形成AD的组织病理学和生化特征：淀粉样斑块、神经原纤维缠结和活化的小胶质细胞。氧化修饰是由糖与蛋白质氨基的非酶反应之后的脱水、氧化和环化反应的复杂级联形成的。一生中AGE交联蛋白的积累是衰老的普遍现象。然而，AGEs不仅仅是衰老的标志物，因为它们还可以对组织和细胞产生不利的生物学效应，包括激活细胞内信号转导通路，导致细胞因子和自由基产生上调（氧化应激）。氧化应激参与导致细胞损伤的各种不同事件，包括膜刚性增加、DNA链断裂和葡萄糖摄取受损。此外，其他与年龄相关的代谢变化，如抗氧化剂耗竭或葡萄糖代谢紊乱导致的能量产生减少，会降低细胞应对自由基诱导的膜、蛋白质和DNA损伤影响的能力。随着我们对痴呆临床症状分子基础的理解不断提高，希望对病因的阐明，特别是涉及自由基损伤和葡萄糖代谢降低的正反馈回路，将有助于开发能够中断AD中氧化应激和能量短缺恶性循环的新型“神经保护”治疗策略。
