Neurotoxicity of .BETA.-amyloid.

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  • KANEKO Isao
    Neuroscience and Immunology Research: Laboratories, SANKYO CO.,LTD.
  • KUBO Takekazu
    Neuroscience and Immunology Research: Laboratories, SANKYO CO.,LTD.
  • MORIMOTO Kiyoshi
    Neuroscience and Immunology Research: Laboratories, SANKYO CO.,LTD.

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  • βアミロイドによる神経細胞毒性
  • ベータ アミロイド ニ ヨル シンケイ サイボウ ドクセイ

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Abstract

Recent observations on the neurotoxicity of β-amyloid have been reviewed and possible roles of racemization of β-amyloid are discussed. β1-40, β25-35 and D-Ser26β25-35 (all HCl salt forms), but not commercially available β1-40 (TFA salt form), take the β-structure within few hours in PBS, form fibrils, exert toxic effects on hippocampal cultured neurons and suppresses MTT reduction activity of non-neuronal HeLa cells without cytotoxicity. D-Ser26β1-40 is soluble and non-toxic in vitro but is converted by brain proteinases to D-Ser26β25-35, a potent toxic and proteinase-resistant fragment. The co-injection of β1-40, D-Ser26β25-35 or D-Ser26β1-40 with ibotenic acid, but not β-amyloid alone or ibotenic acid alone, into rat brains produce drastic neuronal loss in the hippocampal CA1 area. The in vivo degeneration activity of β-amyloids is well correlated with their having β-structure and activity to suppress the MTT reduction activity. A specific antibody against D-Ser26β25-35 strongly reacts with hippocampal degenerated-CA1 neurons in AD but not control brains. These results suggest that D-Ser26β25-35 and related peptides possibly generated from insoluble β1-40 due to aging exert toxic effects on the hippocampal CA1 pyramidal neurons by enhancing the susceptibility to excitatory amino acids.

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