Involvement of Advanced Glycation End-products (AGEs) in Alzheimer's Disease
Involvement of Advanced Glycation End-products (AGEs) in Alzheimer's Disease
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DOI：
10.2174/1567205043480582
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发表时间：
2004-02-01
影响因子：
2.1
通讯作者：
Yamagishi, Sho-ichi
中科院分区：
文献类型：
--
作者：
Takeuchi, Masayoshi;Kikuchi, Seiji;Yamagishi, Sho-ichi
糖化过程的晚期阶段（蛋白质翻译后修饰之一）导致晚期糖基化终产物（AGE）的形成，并在糖尿病患者血管病的发病机制中发挥重要作用。最近人们已经清楚，AGE 还会影响生理衰老和神经退行性疾病，如阿尔茨海默病 (AD) 和肌萎缩侧索硬化症 (ALS)。最近，我们提供了直接的免疫化学证据，证明在血液透析糖尿病患者 (DM-HD) 的血清中循环的 AGE 修饰蛋白和肽中存在六种不同的 AGE 结构。我们展示了合成 AGE-2（甘油醛衍生的 AGE）对皮质神经元细胞的直接毒性作用，并为 DM-HD 血清中存在的 AGE-2 的毒性作用提供了证据。这些结果表明，在体内可形成的各种类型的AGE结构中，AGE-2结构很可能在与AGE形成相关的病理生理过程中发挥重要作用。在AD大脑中，AGE-2表位主要存在于海马和海马旁回神经元的细胞质中。 AGE 结构的蛋白质交联导致形成抗蛋白酶聚集体。这种蛋白质聚集体可能会干扰神经元中的轴突运输和细胞内蛋白质运输。在这篇综述中，我们概述了体内 AGE 的形成，并提出新的结构表位 AGE-2 是 AD 中神经元细胞的重要毒性部分。
The advanced stage of the glycation process (one of the post-translational modifications of proteins) leads to the formation of advanced glycation end-products (AGEs) and plays an important role in the pathogenesis of angiopathy in diabetic patients. It has recently become clear that AGEs also influence physiological aging and neurodegenerative diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS).Recently we have provided direct immunochemical evidence for the existence of six distinct AGE structures within the AGE-modified proteins and peptides that circulate in the serum of diabetic patients on hemodialysis (DM-HD). We showed a direct toxic effect of the synthetic AGE-2 (glyceraldehyde-derived AGEs) on cortical neuronal cells and provided evidence for a toxic effect of AGE-2 present in DM-HD serum. These results indicate that of the various types of AGE structures that can form in vivo, the AGE-2 structure is likely to play an important role in the pathophysiological processes associated with AGE formation.In AD brains, AGE-2 epitope was mainly present in the cytosol of neurons in the hippocampus and para-hipocampal gyrus. Protein cross-linking by AGE structures results in the formation of protease-resistant aggregates. Such protein aggregates may interfere with both axonal transport and intracellular protein traffic in neuron.In this review, we provide an outline of AGEs formation in vivo and propose that the novel structural epitope AGE-2 is an important toxic moiety for neuronal cells in AD.