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2000 Fiscal Year Final Research Report Summary

Neurotoxicity of advanced glycation end products in Alzheimer disease

Research Project

Project/Area Number 11557069
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section展開研究
Research Field Psychiatric science
Research InstitutionKurume University School of Medicine (2000)
Hokkaido University (1999)

Principal Investigator

MAKITA Zenji  Department of Endocrinology and Metabolism, Kurme University School of Medicine, Professor, 医学部, 教授 (50261285)

Co-Investigator(Kenkyū-buntansha) TAKEUCHI Masayoshi  Department of Biochemistry, Faculty of Pharmaceutical Science, Hokuriku University, Assistant Professor, 薬学部, 講師 (20154982)
Project Period (FY) 1999 – 2000
KeywordsAlzheimer disease / Diabetes mellitus / AGE
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.

  • Research Products

    (20 results)

All Other

All Publications (20 results)

  • [Publications] Yamauchi A,Makita Z et al.: "Effects of aminoguanidine on diabetic nephropathy in the OLETF rat, Obesity and NIDDM."Elsevier Science B.V.. 215-221 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tsuchida K,Makita Z et al.: "Suppression of TGF-b and VEGF in diabetic nephropathy in rats by a novel AGE inhibitor, OPB-9195."Diabetologia. 42. 579-588 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kikuchi S,Makita Z et al.: "Neurotoxicity of Methylglyoxal and 3-Deoxyglucosone on cultured corticalneurons. Synergism between glycation and oxidative stress, possibly involved in neurodegenerative diseases."J Neurosci Res. 57. 280-289 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takeuchi M,Makita Z et al.: "Detection of non-carboxymethyllysine and carboxymethyllysine advanced glycation end-products."Mol Med. 5. 393-405 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takeuchi M,Makita Z et al.: "Immunological evidence that non-carboxymethyllysine advanced glycation end-products are produced from short-chain sugars and dicarbonyl compounds in vivo."Mol Med. 6. 114-125 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takeuchi M,Makita Z et al.: "Neurotoxicity of advanced glycation end-products for cultured cortical neurons."J Neuropatho Exp Neur. 59. 1094-1105 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Atsumi T,Makita Z et al.: "Enhancement of oxidized low dinsity lipoprotein uptake by macrophages in response to macrophage migration inhibitory factor."Cytokine. 12. 1553-1556 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Sasaki N,Takeuchi M,Makita Z et al.: "Immunohistochemical distribution of the receptor for advanced glycation end products in neurons and astrocytes in Alzheimer's disease."Brain Res. 888. 256-262 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takeuchi M,Makita Z: "Alternative routes for the formation of Immuno-chemically distinct advanced glycation end-products in vivo."Curr Mol Med. 1(in press). (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kondo T,Higashi H,Nishizawa H,Ishikawa S,Makita Z et al.: "Involvement of pRB-Related p107 Protein in the Inhibition of S-Phase Progression in Response to Genotoxic Stress."J Biol Chem. (in press). (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kondo T, Higashi H, Nishizawa H, Ishikawa S, Ashizawa S, Yamada M, Makita Z, Koike T, Hatakeyama M: "Involvement of pRB-Related p107 Protein in the Inhibition of S-Phase Progression in Response to Genotoxic Stress."J Biol Chem. (in press). (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takeuchi M, Makita Z: "Alternative routes for the formation of Immuno-chemically distinct advanced glycation end-products in vivo."Curr Mol Med 1. (in press). (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Sasaki N, Toki S, Chowei H, Saito T, Nakano N, Hayashi Y, Takeuchi M, Makita Z: "Immunohistochemical distribution of the receptor for advanced glycation end products in neurons and astrocytes in Alzheimer's disease."Brain Res. 888. 256-262 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Atsumi T, Nishihira J, Tsuchida K, Makita Z, Koike T: "Enhancement of oxidized low density lipoprotein uptake by macrophages in response to macrophage migration inhibitory factor."Cytokine. 12. 1553-1556 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takeuchi M, Bucala R, Suzuki T, Ohkubo T, Yamazaki M, Koike T, Kameda Y, Makita Z: "Neurotoxicity of advanced glycation end-products for cultured cortical neurons."J Neuropatho Exp Neur. 59. 1094-1105 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takeuchi M, Makita Z, Bucala R, Suzuki T, Koike T, Kameda Y: "Immunological evidence that non-carboxymethyllysine advanced glycation end-products are produced from short-chain sugars dicarbonyl compounds in vivo."Mol Med. 6. 114-125 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takeuchi M, Yanagisawa K, Koike T, Kamada Y, Makita Z: "Detection of non-carboxymethyllysine and carboxymethyllysine advanced glycation end-products"Mol Med. 5. 393-405 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kikuchi S, Shinpo K, Morikawa F, Makita Z, Mayata T, Tashiro K: "Neurotoxicity of Methylglyoxal and 3-Deoxyglucosone on cultured corticalneurons. Synergism between glycation and oxidative stress, possiblyinvolved in neurodegenerative diseases."J Neurosci Res. 57. 280-289 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tsuchida K, Makita Z, Yamagishi S, Atsumi T, Obara S, Miyoshi H, Ishida M, Ishikawa S, Yasumura K, Koike T: "Suppression of TGF-b and VEGF in diabetic nephropathy in rats by a novel AGE inhibitor, OPB-9195"Diabetologia. 42. 579-588 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yamauchi A, Takei I, Makita Z, Saruta T: "Effects of aminoguanidine on diabetic nephropathy in the OLETF rat, Obesity and NIDDM.In K.Shima.K.ed.Lessons from OLETF Rat."Elsevier Science B.. V.. 215-221 (1999)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2002-03-26  

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