[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.