Involvement of Advanced Glycation End-products (AGEs) in Alzheimer's Disease

被引:118
作者
Takeuchi, Masayoshi [1 ]
Kikuchi, Seiji [2 ]
Sasaki, Nobuyuki [3 ]
Suzuki, Takako [1 ]
Watai, Takayuki [1 ]
Iwaki, Mina [1 ]
Bucala, Richard [4 ,5 ]
Yamagishi, Sho-ichi [6 ]
机构
[1] Hokuriku Univ, Fac Pharmaceut Sci, Dept Biochem, Kanazawa, Ishikawa 9201181, Japan
[2] Hokkaido Univ, Dept Neurol, Grad Sch Med, Sapporo, Hokkaido 0608638, Japan
[3] Sapporo Med Univ, Dept Neuropsychiat, Sapporo, Hokkaido 0608543, Japan
[4] Yale Univ, Dept Med, Sch Med, New Haven, CT 06520 USA
[5] Yale Univ, Dept Pathol, Sch Med, New Haven, CT 06520 USA
[6] Kurume Univ, Dept Med, Sch Med, Kurume, Fukuoka 8300011, Japan
基金
日本学术振兴会;
关键词
advanced glycation end-products (AGEs); glyceraldehyde-derived AGEs; AGE-2; structure; glyceraldehyde-3-phosphate dehydrogenase (GAPDH); Alzheimer's disease (AD); diabetes mellitus (DM); neurotoxicity; apoptosis;
D O I
10.2174/1567205043480582
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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.
引用
收藏
页码:39 / 46
页数:8
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