Takeuchi M, Yamagishi S
Department of Biochemistry, Faculty of Pharmaceutical Sciences, Hokuriku University, Ho-3 Kanagawa-machi, Kanazawa, Ishikawa 920-1181, Japan.
Med Hypotheses. 2004;63(3):453-5. doi: 10.1016/j.mehy.2004.03.005.
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, and in Alzheimer's disease (AD). Recently we have provided direct immunochemical evidence for the existence of six distinct AGEs structures, designated AGEs-1 to -6, within the AGEs-modified proteins and peptides that circulate in the serum of diabetic patients. We found for the first time that glyceraldehyde-derived AGEs (AGE-2), which comprise main structure of TAGE (toxic AGEs), in the serum of diabetic patients have diverse biological activities on vascular wall cells and cortical neurons. These results suggest a causal role for AGE-2 in the pathogenesis of diabetic complications and AD in vivo. In AD brains, AGE-2 epitope was mainly present in the cytosol of neurons in the hippocampus and para-hipocampal gyrus. We propose three pathways for the in vivo formation of AGE-2 precursor, glyceraldehyde, by: (i) glycolytic pathway, (ii) polyol pathway, and (iii) fructose metabolic pathway. Glyceraldehyde can be transported or can leak passively across the plasma membrane. It can react non-enzymatically with proteins to lead to accelerated formation of AGE-2 at both intracellular and extracellular region.
糖基化过程的晚期阶段（蛋白质翻译后修饰之一）会导致晚期糖基化终产物（AGEs）的形成，并且在糖尿病患者的血管病变及阿尔茨海默病（AD）的发病机制中发挥重要作用。最近，我们提供了直接的免疫化学证据，证明在糖尿病患者血清中循环的AGEs修饰的蛋白质和肽内存在六种不同的AGEs结构，命名为AGEs-1至-6。我们首次发现，糖尿病患者血清中构成TAGE（毒性AGEs）主要结构的甘油醛衍生的AGEs（AGE-2），对血管壁细胞和皮质神经元具有多种生物学活性。这些结果表明AGE-2在体内糖尿病并发症和AD的发病机制中起因果作用。在AD大脑中，AGE-2表位主要存在于海马体和海马旁回神经元的细胞质中。我们提出了通过以下三种途径在体内形成AGE-2前体甘油醛：（i）糖酵解途径，（ii）多元醇途径，以及（iii）果糖代谢途径。甘油醛可以被转运或被动地穿过质膜。它可以与蛋白质发生非酶反应，导致细胞内和细胞外区域的AGE-2加速形成。
