The study for neurotoxicity of advanced glycation end-products (the structural epitope AGE-2) in neurodegenerative processes

神经退行性过程中晚期糖基化终产物（结构表位 AGE-2）的神经毒性研究

• 批准号: 13470197
• 负责人: TAKEUCHI Masayoshi
• 金额: $ 8.77万
• 依托单位: Hokuriku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470197/
• 关键词: Advanced glycation end-product; AGE-2 structure; Aβ (1-40); AGE-2 derived Aβ (1-40); Glycation; Alzheimer's disease; neurodegenerative diseases; 神経変性疾患; Advanced Glycation End-product

The Maillard reaction that leads to the formation of advanced glycation end-products (AGEs) plays an important role in the pathogenesis of angiopathy in diabetic patients, in aging and in neurodegenerative processes.1) We developed anti-AGE antibodies that specifically recognize six distinct classes of AGE structures (AGE-1, glucose-derived AGEs, AGE-2, glyceraldehydes-derived AGEs ; AGE-3, glycolaldehyde-derived AGEs ; AGE-4, methylglyoxal- derived AGEs ; AGE-5, glyoxal-derived AGEs ; and AGE-6, 3-deoxyglucosone-derived AGEs) within the circulating proteins and peptides present in serum from diabetic patients on hemodialysis.2) We recently reported that an elevation of serum AGE levels was found to be associated with severity of diabetic retinopathy. We also reported that AGEs in the serum of diabetic patients on hemodialysis have diverse biological activities on vascular wall, kidney mesangial and cortical neuronal cells. Therefore, these results suggest a causal role for these types … More of AGEs in the pathogenesis of diabetic complication and neurodegenerative disease.3) Incubation of cortical neurons with six immunochemically distinct AGEs, designated AGEs-1 to -6, produced a dose-dependent increase in neuronal cell-death. The structural epitope designated AGE-2 (glyceraldehyde-derived AGEs) was found to have the greatest cytopathic effect and the neurotoxicity of AGE-2 was neutralized by the addition of an anti-AGE-2 specific antibody. We provide the first evidence for the toxicity of a specific AGE structure, defined as AGE-2, on rat primary cultured cortical neuronal cells.4) The immunohistochemical study showed that AGE-2 existed in the Alzheimer's brain. The AGE-2 was mainly localized in the cytosol of neurons, not in the nucleus, astrocytes, and extracellular area. Senile plaques were not stained with the anti-AGE-2 antibody. There was no difference in neurotoxicity between AGE-2-Aβ and Aβ only. These results suggested that AGE-2 promotes neurotoxicity without reference to Aβ. We hypothesized that the AGE-2 immunopositive reaction in the pericaryon reflects the increase generation of AGE-2 in cytoplasm that occurs with the decline of GAPDH.5) Recently, it has become clear that AGEs also have a role in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, and amyotrophic lateral sclerosis (ALS). Less

项目成果

佐々木信幸, 竹内正義 他6名: "Immunohistochemical distribution of the receptor for advanced glycation end products in neurons and astrocytes in Alzheimer's disease"Brain Res.. 888(2). 256-262 (2001)

Nobuyuki Sasaki、Masayoshi Takeuchi 等 6 人：“阿尔茨海默病神经元和星形胶质细胞中高级糖基化终产物受体的免疫组织化学分布”Brain Res.. 888(2) (2001)。

山岸昌一, 竹内正義 他4名: "Beraprost sodium, a prostaglandin I_2 analogue, protects against advanced glycation end products-induced injury in cultured retinal pericytes"Mol. Med.. 8. 546-550 (2002)

Shoichi Yamagishi、Masayoshi Takeuchi 等 4 人：“贝前列素钠，一种前列腺素 I_2 类似物，可防止培养的视网膜周细胞中晚期糖基化终产物诱导的损伤”Mol. 8. 546-550 (2002)

Yamamoto Y, Kato I, Doi T, Yonekura H, Ohashi S, Takeuchi M, Watanabe T, Yamagishi S, Sakurai S, Takasawa S, Okamoto H, and Yamamoto H: "Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice"J. Clin. Invest.. 108. 261-268

Yamamoto Y、Kato I、Doi T、Yonekura H、Ohashi S、Takeuchi M、Watanabe T、Yamagishi S、Sakurai S、Takasawa S、Okamoto H 和 Yamamoto H：“RAGE 过表达小鼠晚期糖尿病肾病的发生和预防

Yamagishi S, Takeuchi M and Makita Z: "Advanced glycation end products and the pathogenesis of diabetic nephripathy"Contrib. Nephrol.. 134. 30-35 (2001)

Yamagishi S、Takeuchi M 和 Makita Z：“晚期糖基化终末产物和糖尿病肾病的发病机制”Contrib。

古賀康八郎, 竹内正義 他5名: "Serum levels of glucose-derived advanced glycation end products are associated with the severity of diabetic retinopathy in type 2 diabetic patients without renal dysfunction"Int. J. Clin. Pharm. Res.. 22. 23-27 (2002)

Kohachiro Koga、Masayoshi Takeuchi 等 5 人：“葡萄糖衍生的晚期糖基化终产物的血清水平与无肾功能障碍的 2 型糖尿病患者的糖尿病视网膜病变的严重程度相关”，《Int. Res.》22。 23-27 (2002)