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The Journal of Neuroscience, May 19, 2004, 24(20):4894-4902; doi:10.1523/JNEUROSCI.0861-04.2004

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 Previous Article

Neurobiology of Disease
A Seed for Alzheimer Amyloid in the Brain

Hideki Hayashi,1 Nobuyuki Kimura,2 Haruyasu Yamaguchi,3 Kazuhiro Hasegawa,4 Tatsuki Yokoseki,5 Masao Shibata,5 Naoki Yamamoto,1 Makoto Michikawa,1 Yasuhiro Yoshikawa,2 Keiji Terao,6 Katsumi Matsuzaki,7 Cynthia A. Lemere,8 Dennis J. Selkoe,8 Hironobu Naiki,4 and Katsuhiko Yanagisawa1

1Department of Dementia Research, National Institute for Longevity Sciences, Obu 474-8522, Japan, 2Department of Biomedical Science, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan, 3Gunma University School of Health Sciences, Maebashi 371-8514, Japan, 4Division of Molecular Pathology, Department of Pathological Sciences, Faculty of Medical Sciences, University of Fukui, Matsuoka 910-1193, Japan, 5Department of Pharmaceutical Development, Ina Institute, Medical and Biological Laboratories Company Ltd., Terasawaoka, Ina 396-0002, Japan, 6Tsukuba Primate Center for Medical Sciences, National Institute for Infectious Diseases, Hachimandai, Tsukuba 305-0843, Japan, 7Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan, and 8Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts 02115

A fundamental question about the early pathogenesis of Alzheimer's disease (AD) concerns how toxic aggregates of amyloid {beta} protein (A{beta}) are formed from its nontoxic soluble form. We hypothesized previously that GM1 ganglioside-bound A{beta} (GA{beta}) is involved in the process. We now examined this possibility using a novel monoclonal antibody raised against GA{beta} purified from an AD brain. Here, we report that GA{beta} has a conformation distinct from that of soluble A{beta} and initiates A{beta} aggregation by acting as a seed. Furthermore, GA{beta} generation in the brain was validated by both immunohistochemical and immunoprecipitation studies. These results imply a mechanism underlying the onset of AD and suggest that an endogenous seed can be a target of therapeutic strategy.

Key words: Alzheimer's disease; amyloid; amyloid {beta} protein; seed; ganglioside; raft

Received Dec 26, 2003; revised April 14, 2004; accepted April 15, 2004.




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