[Neurotoxicity of beta-amyloid].
Recent observations on the neurotoxicity of beta-amyloid have been reviewed and possible roles of racemization of beta-amyloid are discussed. beta 1-40, beta 25-35 and D-Ser26 beta 25-35 (all HCl salt forms), but not commercially available beta 1-40 (TFA salt form), take the beta-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-Ser26 beta 1-40 is soluble and non-toxic in vitro but is converted by brain proteinases to D-Ser26 beta 25-35, a potent toxic and proteinase-resistant fragment. The co-injection of beta 1-40, D-Ser26 beta 25-35 or D-Ser26 beta 1-40 with ibotenic acid, but not beta-amyloid alone or ibotenic acid alone, into rat brains produce drastic neuronal loss in the hippocampal CA1 area. The in vivo degeneration activity of beta-amyloids is well correlated with their having beta-structure and activity to suppress the MTT reduction activity. A specific antibody against D-Ser26 beta 25-35 strongly reacts with hippocampal degenerated-CA1 neurons in AD but not control brains. These results suggest that D-Ser26 beta 25-35 and related peptides possibly generated from insoluble beta 1-40 due to aging exert toxic effects on the hippocampal CA1 pyramidal neurons by enhancing the susceptibility to excitatory amino acids.
Kaneko
I
I
Neuroscience and Immunology Research Laboratories, SANKYO CO., LTD., Tokyo, Japan.
Kubo
T
T
Morimoto
K
K
D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D018846:Excitatory Amino Acids / Q000633:toxicity; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D009410:Nerve Degeneration; D010084:Oxidation-Reduction; D051381:Rats; D012995:Solubility; D013237:Stereoisomerism; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism
D016229:Amyloid beta-Peptides; D018846:Excitatory Amino Acids; D013778:Tetrazolium Salts; D013844:Thiazoles