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Acta Neuropathologica

, Volume 97, Issue 3, pp 240–246 | Cite as

Advanced glycation endproducts are deposited in neuronal hyaline inclusions: a study on familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation

  • N. Shibata
  • Asao Hirano
  • Shinsuke Kato
  • Ryoji Nagai
  • Seikoh Horiuchi
  • Takashi Komori
  • Takahiko Umahara
  • Kohtaro Asayama
  • Makio Kobayashi
Regular paper

Abstract

To determine the role of advanced glycation endproducts (AGE) in the pathogenesis of familial amyotrophic lateral sclerosis (ALS) with superoxide dismutase-1 (SOD1) mutation, we investigated the immunohistochemical localization of Nɛ-carboxymethyl-lysine (CML), one of the major AGE structures, in spinal cords from three familial ALS patients with a heterozygous Ala to Val substitution at codon 4 in the gene for SOD1. Neuronal hyaline inclusions (NHIs), the abnormal structures seen in some of the remaining lower motor neurons of familial ALS patients with SOD1 mutation, were intensely stained by a monoclonal antibody specific for CML in contrast to the only weakly stained cytoplasm. Immunoelectron microscopy depicted the CML determinants restricted to the granule-associated thick linear structures that mainly compose the NHIs. The NHIs were also recognized by antibodies to SOD1, phosphorylated neurofilament protein and ubiquitin. No focal collection of either CML or SOD1 was found in neurons of the control individuals. Our results indicate that CML is a component of the NHIs of familial ALS patients with SOD1 mutation, and suggest that the CML formation may be mediated by protein glycoxidation or lipid peroxidation in the presence of oxidative stress from mutant SOD1, in association with motor neuron degeneration.

Key words Amyotrophic lateral sclerosis Advanced glycation endproducts Immunohistochemistry Superoxide dismutase Hyaline inclusions 

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Copyright information

© Springer-Verlag Berlin Heidelberg 1999

Authors and Affiliations

  • N. Shibata
    • 1
  • Asao Hirano
    • 2
  • Shinsuke Kato
    • 3
  • Ryoji Nagai
    • 4
  • Seikoh Horiuchi
    • 4
  • Takashi Komori
    • 5
  • Takahiko Umahara
    • 6
  • Kohtaro Asayama
    • 7
  • Makio Kobayashi
    • 1
  1. 1.Department of Pathology, Tokyo Women’s Medical College, Kawada-cho 8-1, Shinjuku-ku, Tokyo 162, Japan Tel.: +81-3-3353-8111 (ext. 22 233), Fax: +81-3-5269-7408JP
  2. 2.Division of Neuropathology, Department of Pathology, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10 467–2490, USAUS
  3. 3.Division of Neuropathology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, Nishi-machi 86, Yonago 683, JapanJP
  4. 4.Department of Biochemistry, Kumamoto University School of Medicine, Honjo 2-2-1, Kumamoto 860, JapanJP
  5. 5.Department of Clinical Neuropathology, Tokyo Metropolitan Institute for Neuroscience, Musashidai 2-6, Fuchu, Tokyo 183, JapanJP
  6. 6.Department of Geriatrics, Tokyo Medical College, Nishishinjuku 6-7-1, Shinjuku-ku, Tokyo 160, JapanJP
  7. 7.Department of Pediatrics, Yamanashi Medical College, Shimokato 1110, Tamaho-cho, Nakakoma-gun, Yamanashi 409-38, JapanJP

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