| Project/Area Number |
11557069
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Psychiatric science
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| Research Institution | Kurume University School of Medicine (2000)
Hokkaido University (1999) |
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Principal Investigator |
MAKITA Zenji Department of Endocrinology and Metabolism, Kurme University School of Medicine, Professor, 医学部, 教授 (50261285)
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| Co-Investigator(Kenkyū-buntansha) |
TAKEUCHI Masayoshi Department of Biochemistry, Faculty of Pharmaceutical Science, Hokuriku University, Assistant Professor, 薬学部, 講師 (20154982)
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| Project Period (FY) |
1999 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥12,200,000 (Direct Cost: ¥12,200,000)
Fiscal Year 2000: ¥5,700,000 (Direct Cost: ¥5,700,000)
Fiscal Year 1999: ¥6,500,000 (Direct Cost: ¥6,500,000)
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| Keywords | Alzheimer disease / Diabetes mellitus / AGE / 神経変性疾患 / 病理学 |
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| Research Abstract |
Accumulation of advanced glycation end products (AGE) plays an important role in the pathogenesis of diabetic vascular complications. Recently, AGE are reported also to contribute to the pathology of Alzheimer's disease (AD) and other neurodegenerative processes. However, the molecular mechanism underlying this remains to be elucidated. Here we prepared five immunochemically distinct AGE, designated AGE-1 to-5, and further investigated their effects on neuronal cell death. Incubation of rat cortical neurons with AGE-1 to -5 produced a dose-dependent increase in neuronal cell-death, as assessed by MTT assay, Trypan blue and Hoechst 33258 staining. The structural epitope designated AGE-2 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, but not by other types of anti-AGE antibodies. Distinct classes of AGE structures also have been established to circulate in the blood of individuals with diabetes mellitus and end-stage renal disease treated by hemodialysis (DM-HD). We fractionated serum from normal control and DM-HD patients by gel filtration and identified two fractions that contained AGE epitopes-1 to-5 and as well as the defined AGE structure carboxymethyllysine. The addition of these two fractions led to the death of cultured neuronal cells and this cytotoxic effect was also completely prevented by the addition of the anti-AGE-2 specific antibody. We propose that the structural epitope AGE-2 is an important toxic moiety for neuronal cells in vivo.
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